Strategies for halting the rise of multidrug resistant TB epidemics: assessing the effect of early case detection and isolation.

PubMed

Espindola, Aquino L; Varughese, Marie; Laskowski, Marek; Shoukat, Affan; Heffernan, Jane M; Moghadas, Seyed M

2017-03-01

The increasing rates of multidrug resistant TB (MDR-TB) have posed the question of whether control programs under enhanced directly observed treatment, short-course (DOTS-Plus) are sufficient or implemented optimally. Despite enhanced efforts on early case detection and improved treatment regimens, direct transmission of MDR-TB remains a major hurdle for global TB control. We developed an agent-based simulation model of TB dynamics to evaluate the effect of transmission reduction measures on the incidence of MDR-TB. We implemented a 15-day isolation period following the start of treatment in active TB cases. The model was parameterized with the latest estimates derived from the published literature. We found that if high rates (over 90%) of TB case identification are achieved within 4 weeks of developing active TB, then a 15-day patient isolation strategy with 50% effectiveness in interrupting disease transmission leads to 10% reduction in the incidence of MDR-TB over 10 years. If transmission is fully prevented, the rise of MDR-TB can be halted within 10 years, but the temporal reduction of MDR-TB incidence remains below 20% in this period. The impact of transmission reduction measures on the TB incidence depends critically on the rates and timelines of case identification. The high costs and adverse effects associated with MDR-TB treatment warrant increased efforts and investments on measures that can interrupt direct transmission through early case detection. © The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The development, evaluation and performance of molecular diagnostics for detection of Mycobacterium tuberculosis.

PubMed

Bates, Matthew; Zumla, Alimuddin

2016-01-01

The unique pathogenesis of tuberculosis (TB) poses several barriers to the development of accurate diagnostics: a) the establishment of life-long latency by Mycobacterium tuberculosis (M.tb) after primary infection confounds the development of classical antibody or antigen based assays; b) our poor understanding of the molecular pathways that influence progression from latent to active disease; c) the intracellular nature of M.tb infection in tissues means that M.tb and/or its components, are not readily detectable in peripheral specimens; and d) the variable presence of M.tb bacilli in specimens from patients with extrapulmonary TB or children. The literature on the current portfolio of molecular diagnostics tests for TB is reviewed here and the developmental pipeline is summarized. Also reviewed are data from recently published operational research on the GeneXpert MTB/RIF assay and discussed are the lessons that can be taken forward for the design of studies to evaluate the impact of TB diagnostics.

Activities of the Korean Institute of Tuberculosis

PubMed Central

Ryoo, Sungweon; Kim, Hee Jin

2014-01-01

The Korean National Tuberculosis Association (KNTA) set up the Korean Institute of Tuberculosis (KIT) in 1970 to foster research and technical activities pertaining to tuberculosis (TB). The KNTA/KIT had successfully conducted a countrywide TB prevalence survey from 1965 to 1995 at 5-year intervals. The survey results (decline in TB rates) established Korea as a country that had successfully implemented national control programs for TB. The KIT developed the Korea Tuberculosis Surveillance System and the Laboratory Management Information System, both of which were transferred to the Korea Centers for Disease Control and Prevention after its establishment. The KIT functions as a central and supranational reference TB laboratory for microbiological and epidemiological research and provides training and education for health-care workers and medical practitioners. Recently, the KIT has expanded its activities to countries such as Ethiopia, Laos, and Timor-Leste to support TB control and prevention. The KIT will continue to support research activities and provide technical assistance in diagnosing the infection until it is completely eliminated in Korea. PMID:25861580

Active Tuberculosis in HIV-Exposed Tanzanian Children up to 2 years of Age: Early-Life Nutrition, Multivitamin Supplementation and Other Potential Risk Factors.

PubMed

Olofin, Ibironke O; Liu, Enju; Manji, Karim P; Danaei, Goodarz; Duggan, Christopher; Aboud, Said; Spiegelman, Donna; Fawzi, Wafaie W

2016-02-01

Over half a million children worldwide develop active tuberculosis (TB) each year. Early-life nutritional exposures have rarely been examined in relation to pediatric TB among HIV-exposed children. We therefore investigated independent associations of early-life nutritional exposures with active TB among HIV-exposed children up to 2 years of age. Participants were children from a randomized controlled multivitamin supplementation trial conducted in Dar es Salaam, Tanzania, from August 2004 to May 2008, who received daily multivitamin supplements or placebo for 24 months. Lower mean corpuscular volumes [relative risks (RR): 0.48, 95% confidence interval (CI): 0.27, 0.87] and higher birth weights (RR: 0.61, 95% CI: 0.37, 0.99) were protective against active TB, whereas multivitamin supplementation was not associated with TB risk (RR: 0.87, 95% CI: 0.65, 1.16). Knowledge of nutrition-related risk and protective factors for TB in HIV-exposed children could enhance preventive and case-finding activities in this population, contributing to efforts to reduce the global TB burden. © The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

New diagnostics for latent and active tuberculosis: state of the art and future prospects.

PubMed

Pai, Madhukar; O'Brien, Richard

2008-10-01

Tuberculosis (TB) continues to be the world's most important infectious cause of morbidity and mortality among adults. Nearly 9 million people develop TB disease each year, and an estimated 1.6 million die from the disease. Despite this enormous global burden, case detection rates are low, posing serious hurdles for TB control. Conventional TB diagnosis continues to rely on antiquated tests such as sputum smear microscopy, culture, tuberculin skin test, and chest radiography. These tests have several limitations and perform poorly in populations affected by the HIV epidemic. Conventional tests for detection of drug resistance are time consuming, tedious, and inaccessible in most settings. In this review, we describe recent advances in the diagnosis of latent and active TB, and detection of drug resistance. Although the perfect test will not be ready for large-scale roll-out and integration into routine TB care services for some time, substantial progress has been made in expanding the TB diagnostic product pipeline. With the resurgence of interest in the development of new tools for TB control, and the recent influx of funding and political support, it is likely that the next few years will see the introduction of new diagnostic tools into routine TB control programs.

The Association Between Lung Carcinoma and Tuberculosis

PubMed Central

Cukic, Vesna

2017-01-01

Introduction: The association between lung tuberculosis and lung carcinoma is still controversial. Objective: to describe the characteristics of patients with associated lung tuberculosis (TB) and lung carcinoma (LC) in patients treated in Clinic for pulmonary diseases and TB “Podhrastovi”. Material and Methods: This is the retrospective study of patients with LC associated with TB treated in Clinic for pulmonary diseases and TB “Podhrastovi” in five-year period -from 2012 to 2016. We analyzed sex and age of patients, whether TB preceded LC or LC preceded TB, a time period between the developments of these two diseases, activity of TB, the histopathological type of LC, localization of LC in lungs (bronchial, peripheral, cavern) according to histopathological type. Results: In this period there were 2608 patients treated for LC. Among them there were 34 patients with diagnosed TB or 1.3%. All of them were smokers. No one had active TB. TB was the first diagnosis in all these patients. Each patient was previously treated for TB in hospital and had regular anti TB treatment. TB preceded LC in median time of 5 years (interquartile range 2 to 25 years). In 21 cases it was carcinoma of the drainage bronchus, in 11 cases it was peripheral lung carcinoma and 2 cases it was cavern carcinoma. Conlusion: patients with cured pulmonary tuberculosis represent a group at risk for developing lung carcinoma. Changes in the bronchial and alveolar mucosa which tuberculosis leaves behind in the lungs must be taken as a possible place of later malignant alteration. Patients with any form of pulmonary tuberculosis have to be controlled continuously. PMID:28974836

IL-6 release of Rv0183 antigen-stimulated whole blood is a potential biomarker for active tuberculosis patients.

PubMed

Liu, Yongliang; Li, Xiaofei; Liu, Wei; Liu, Yang; Zhong, Zhouyue; Wang, Lili; Ge, ShengXiang; Zhang, Jun; Xia, Ningshao

2018-04-01

New tests for diagnosing active tuberculosis (aTB) are urgently needed, and TB antigen-specific cell-mediated immunity can be expected to develop new testing methods of aTB. Rv0183 protein, the only monoglyceride lipase identified in mycobacteria, was used to stimulate freshly heparin-treated whole blood. The Rv0183-specific cytokines/chemokines response associated with aTB was screened firstly with 4 aTB patients and 4 LTBIs, and further evaluated in 192 suspected aTB patients and 372 healthy individuals. Out of 71 cytokines/chemokines, the response of IL-6 against Rv0183 protein was found to be associated with aTB. The Rv0183-specific IL-6 response was significantly higher in aTB patients (n = 128) than in those with non-TB lung disease (n = 64) and in healthy individuals (n = 327) (p < 0.0001), and not affected by latent TB infection. In IGRA+ suspected active TB patients, the sensitivity, specificity, PPV and NPV of IL-6 response (with cutoff of 235.2 pg/ml) were 85.7%, 100%, 100% and 51.5% for diagnosing aTB, respectively. While in IGRA- ones, they were 87.5%, 80.5%, 60.9% and 95.0% with 174.2 pg/ml IL-6 response as cutoff, respectively. These results clearly show that the Rv0183 antigen-specific IL-6 response has the potential to be used as an immune-diagnosis test for active TB in clinical practice. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Selected risk factors associated with pulmonary tuberculosis among Saharia tribe of Madhya Pradesh, central India.

PubMed

Rao, Vikas G; Gopi, P G; Bhat, Jyothi; Yadav, Rajiv; Selvakumar, N; Wares, Douglas F

2012-04-01

Tuberculosis (TB) is a major public health problem among the Saharia, a marginalized tribal group in Madhya Pradesh state, central India. However, there is no information on the risk factors associated with the development of TB disease in this community. A cross-sectional TB prevalence survey was conducted among the Saharia residing in Sheopur district of Madhya Pradesh. Information on tobacco smoking and alcohol consumption was collected from all the individuals. Persons aged ≥45 years, males, smokers and alcohol consumers had higher risks of developing TB disease. There is an urgent need to develop and implement culturally appropriate awareness raising activities to target smoking and alcohol consumption to support the efforts to control TB in this community.

Combined IFN-γ and TNF-α release assay for differentiating active tuberculosis from latent tuberculosis infection.

PubMed

Kim, Ji Yeun; Park, Joung Ha; Kim, Min-Chul; Cha, Hye Hee; Jeon, Na-Young; Park, Seong Yeon; Kim, Min-Jae; Chong, Yong Pil; Lee, Sang-Oh; Choi, Sang-Ho; Kim, Yang Soo; Woo, Jun Hee; Kim, Sung-Han

2018-05-08

The IFN-γ-release assay (IGRA) cannot differentiate active tuberculosis (TB) from latent TB infection (LTBI). We hypothesized that the TNF-α-release assay (TARA) combined with IGRA might discriminate active TB from not active TB without LTBI. Adult patients with suspected TB, and with unrelated diseases such as herpes zoster as controls, were enrolled in an intermediate TB-burden country. Patients with confirmed or probable TB were regarded as active TB, and patients with not active TB were further classified as those having not active TB with and without LTBI based on IGRA results. The IGRA and TARA by using ELISPOT assays were performed on peripheral mononuclear cells. Thirty six patients with active TB and 53 patients including 18 not active TB with LTBI and 35 not active TB without LTBI were finally included. The sensitivity and specificity of the IGRA for those patients found to have active TB were 94% (CI, 80-99) and 66% (CI 52-78), respectively. Combining the IGRA and the TARA substantially increased the specificity for active TB (93%, CI, 82-98; P = 0.001) compared with the IGRA only, without compromising sensitivity (89%, CI, 73-96; P = 0.67). Combining the IGRA and TARA appears to be useful for diagnosing active TB. Copyright © 2018. Published by Elsevier Ltd.

Isoniazid for preventing tuberculosis in HIV-infected children

PubMed Central

Zunza, Moleen; Gray, Diane M; Young, Taryn; Cotton, Mark; Zar, Heather J

2017-01-01

Background Tuberculosis (TB) is an important cause of illness and death in HIV-positive children living in areas of high TB prevalence. We know that isoniazid prophylaxis prevents TB in HIV-negative children following TB exposure, but there is uncertainty related to its role in TB preventive treatment in HIV-positive children. Objectives To summarise the effects of TB preventive treatment versus placebo in HIV-positive children with no known TB contact on active TB, death, and reported adverse events. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, Embase and two trial registers up to February 2017. Selection criteria We included trials of HIV-positive children with and without known TB exposure, randomized to receive TB preventive treatment or placebo. Data collection and analysis Two review authors independently used the study selection criteria, assessed risk of bias, and extracted data. We assessed effects using risk, incidence rate and hazard ratios and assessed the certainty of evidence using GRADE. Main results We included three trials, involving 991 participants, below the age of 13 years, from South Africa and Botswana. Children were randomized to isoniazid prophylaxis or placebo, given daily or three times weekly. The median length of follow-up ranged from 5.7 to 34 months; some were on antiretroviral therapy (ART). In HIV-positive children not on ART, isoniazid prophylaxis may reduce the risk of active TB (hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.11 to 0.87; 1 trial, 240 participants, low certainty evidence), and death (HR 0.46, 95% CI 0.22 to 0.95; 1 trial, 240 participants, low certainty evidence). One trial (182 participants) reported number of children with laboratory adverse events, which was similar between the isoniazid prophylaxis and placebo groups. No clinical adverse events were reported. In HIV-positive children on ART, we do not know if isoniazid prophylaxis reduces the risk of active TB (risk ratio (RR) 0.76, 95% CI 0.50 to 1.14; 3 trials, 737 participants, very low certainty evidence) or death (RR 1.45, 95% CI 0.78 to 2.72; 3 trials, 737 participants, very low certainty evidence). Two trials (714 participants) reported number of clinical adverse events and three trials (795 participants) reported number of laboratory adverse events; for both categories, the number of adverse events were similar between the isoniazid prophylaxis and placebo groups. Authors' conclusions Isoniazid prophylaxis given to all children diagnosed with HIV may reduce the risk of active TB and death in HIV-positive children not on ART in studies from Africa. For children on ART, no clear benefit was detected. . Isoniazid prophylaxis for preventing active tuberculosis and death in HIV-positive children What was the aim of this review? To summarise the effects of isoniazid prophylaxis on TB, death, and adverse effects in HIV-positive children. Key messages In areas of high tuberculosis endemicity, isoniazid prophylaxis prevents active TB and death in HIV-positive children who are not on ART. We conducted a review to assess the effect of TB medication on active TB or death and its safety in HIV-positive children. What was studied in the review? TB is a common cause of severe lung disease and death in HIV-positive children. Childhood TB is common in poor countries, especially those with a coexisting burden of HIV/AIDS disease. HIV-positive children have a higher risk of developing TB than HIV-negative children. Isoniazid prevents TB in HIV-positive adults and is currently used in children who are at high risk of developing TB disease after exposure to someone with TB. However, there is limited information on the effect of isoniazid medication in reducing active TB or death if given to HIV-positive children without known TB contact. We searched for studies up to 17 February 2017, and found three studies published between 2007 and 2014 that addressed the effect of isoniazid medication compared to no medication on active TB and death in 991 HIV-positive children, below the age of 13 years. Most of the children were on antiretroviral therapy (ART) and the studies were conducted in South Africa and Botswana. The median length of follow-up ranged from 5.7 to 34 months. What are the main results of the review? In HIV-positive children not taking ART, isoniazid medication reduced the number of children developing active TB by 69% (low certainty evidence), and death by 54% (low certainty evidence). One trial was conducted in HIV-positive children taking ART, and this did not detect any benefit or harm of isoniazid (very low certainty evidence). The number of children with adverse effects were similar in children receiving isoniazid medication as the control group in both children on ART and not on ART. How up to date is the review? The review authors searched for studies published up to February 2017. PMID:28850172

Mini epidemic of isoniazide resistant TB in rural TN: a need for supervised preventive therapy.

PubMed

Mehta, Jay; Keith, Rob; Al Hasan, Muhannad; Ryland, Byrd; Roy, Thomas

2009-08-01

With the resurgence of tuberculosis (TB) in the late 1980s, multi-drug-resistant TB (MDR-TB) also became a serious challenge to the TB control programs across the United States (US). While the incidence of TB resumed a downward trend in the mid 1900s, drug-resistant TB continues to be a national and international problem. We reviewed the public health data of drug-resistant TB cases (1996-2002) in Greene County, TN, with a detailed analysis of their contact investigation. Our study included demographic data of age, sex, race, human immunodeficiency virus (HIV) status and other known risk factors for drug-resistant TB. Contact investigation of two patients with isoniazide-resistant active pulmonary TB led to the discovery of two additional cases of active pulmonary tuberculosis, one of them being a 14-month-old child. All four of the patients were U.S. born, had negative HIV tests, and lacked other risk factors for drug-resistant TB. In all four cases, the Mycobacterium tuberculosis isolates were resistant to isoniazide, three were streptomycin resistant, and was ethambutol resistant. A total of 65 close contacts were identified, 11 of whom had a positive purified protein derivative (PPD) skin test indicating latent TB infection. Based on the American Thoracic Society's recommendations, the contacts with a positive PPD were prescribed rifampin for chemo-prevention rather than INH. However, one active case was detected from this infected contact who had failed to comply with chemo-preventive therapy. The second active case was a child who developed active pulmonary TB before chemoprevention could be initiated. Drug culture profile and DNA analysis (RFLP) confirmed the same source for TB transmission. The 11/65 (16.5 percent) infection rate among the contact was comparable to the state average (p < 0.05), but the case rate of 4/65 (6.15 percent) was high. In two out of four active cases, who were family members of the known cases, active infection could have been prevented. High prevalence of drug-resistant TB in rural areas without any known risk factors and failure of prevention are crucial findings of our study. Clinicians practicing in a rural setting should be aware of occasional mini-outbreaks of drug-resistant TB. Supervised therapy for rifampin chemo-prophylaxis and other standard public health measures successfully controlled this mini-epidemic. Awareness of drug resistance in family clusters and an urgent need for prompt chemo-preventive measures are important in implementing successful TB control programs.

Enhanced laboratory capacity development: a boost for effective tuberculosis control in resource-limited settings.

PubMed

Alabi, Abraham Sunday; Traoré, Afsatou Ndama; Loembe, Marguerite Massinga; Ateba-Ngoa, Ulysse; Frank, Matthias; Adegnika, Ayola Akim; Lell, Bertrand; Mahoumbou, Jocelyn; Köhler, Carsten; Kremsner, Peter Gottfried; Grobusch, Martin Peter

2017-03-01

Both routine and research tuberculosis (TB) laboratory capacity urgently need to be expanded in large parts of Sub-Saharan Africa. In 2009, the Centre de Recherches Médicales de Lambaréné (CERMEL) took a strategic decision to expand its activities by building TB laboratory capacity to address research questions and to improve routine diagnostic and treatment capacity. Over the past 7 years, a standard laboratory has been developed that is contributing significantly to TB diagnosis, treatment, and control in Gabon; training has also been provided for TB research staff in Central Africa. CERMEL has a cordial relationship with the Gabon National TB Control Programme (PNLT), which has culminated in a successful Global Fund joint application. This endeavour is considered a model for similar developments needed in areas of high TB prevalence and where TB control remains poor to date. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Transient expansion of activated CD8+ T cells characterizes tuberculosis-associated immune reconstitution inflammatory syndrome in patients with HIV: a case control study

PubMed Central

2013-01-01

Background CD4+ T cell activation indicators have been reported to be a common phenomenon underlying diverse manifestations of immune reconstitution inflammatory syndrome (IRIS). However, we have found that a high frequency of circulating CD8+ T cells is a specific risk factor for mycobacterial IRIS. Therefore, we investigated whether CD8+ T cells from patients who develop TB IRIS were specifically activated. Methods We obtained PBMCs from HIV+ patients prior to and 4, 8, 12, 24, 52 and 104 weeks after initiating antiretroviral therapy. CD38 and HLADR expression on naive, central memory and effector memory CD8+ and CD4+ T cells were determined by flow cytometry. Absolute counts and frequencies of CD8+ T cell subsets were compared between patients who developed TB IRIS, who developed other IRIS forms and who remained IRIS-free. Results TB IRIS patients showed significantly higher counts of naive CD8+ T cells than the other groups at most time points, with a contraction of the effector memory subpopulation occurring later in the follow-up period. Activated (CD38+ HLADR+) CD8+ T cells from all groups decreased with treatment but transiently peaked in TB IRIS patients. This increase was due to an increase in activated naive CD8+ T cell counts during IRIS. Additionally, the CD8+ T cell subpopulations of TB IRIS patients expressed HLADR without CD38 more frequently and expressed CD38 without HLADR less frequently than cells from other groups. Conclusions CD8+ T cell activation is specifically relevant to TB IRIS. Different IRIS forms may involve different alterations in T cell subsets, suggesting different underlying inflammatory processes. PMID:23688318

Latent tuberculosis infection among close contacts of multidrug-resistant tuberculosis patients in central Taiwan.

PubMed

Huang, Y-W; Shen, G-H; Lee, J-J; Yang, W-T

2010-11-01

Both the tuberculin skin test (TST) and the QuantiFERON®-TB Gold In-Tube test (QFT-GIT) may be used to detect Mycobacterium tuberculosis infection. A positive reaction to either test can indicate latent tuberculosis infection (LTBI). These tests can be used to study the rate of infection in contacts of multidrug-resistant tuberculosis (MDR-TB) patients. To evaluate the transmission status of MDR-TB patients in Taiwan by examining their close contacts and to compare the efficiency of TST and QFT-GIT. Chest radiographs, TST and QFT-GIT were performed in household contacts of confirmed MDR-TB patients to determine their infection status. A total of 78 close contacts of confirmed MDR-TB patients were included in the study. The majority of the MDR-TB patients were parents of the close contacts and lived in the same building; 46% of the subjects were TST-positive and 19% were QFT-GIT-positive, indicating LTBI that was likely to develop into active MDR-TB. There was a lack of consistency between TST and QFT-GIT results in subjects with previous bacille Calmette-Guérin vaccination. Household contacts of MDR-TB patients are likely to develop LTBI; thus, follow-up and monitoring are mandatory to provide treatment and reduce the occurrence of active infection.

Fast and efficient detection of tuberculosis antigens using liposome encapsulated secretory proteins of Mycobacterium tuberculosis.

PubMed

Tiwari, Dileep; Haque, Shafiul; Tiwari, Ram P; Jawed, Arshad; Govender, Thavendran; Kruger, Hendrik G

2017-04-01

A rapid and efficient diagnostic test was developed for the detection of Mycobacterium tuberculosis antigens in serum samples of active tuberculosis (TB) and extrapulmonary TB patients via a liposomal agglutination-based method. A rapid card test has been developed to facilitate the recognition of high-affinity binding rabbit raised purified culture filtrate protein antibodies coupled on the surface of activated liposomal preparation. In the presence of TB antigens, the polyclonal antibodies bound to the liposomal particles demonstrate a visible agglutination reaction. The developed assay was simple, rapid, reliable, sensitive, and specific as a diagnostic test for the detection of antigens in serum samples of clinically confirmed cases of TB within 4-5 minutes' duration. The test was evaluated at different hospitals, medical colleges, and pathology centers, and involved 1483 participants. This investigation was conducted to detect the presence of these antigens during the period of active growth of the microorganism in serum samples for pulmonary TB and processed tissue biopsy for other extrapulmonary TB. Results obtained using this test were compared with acid-fast bacilli smear and culture results. Our study demonstrated that the newly developed liposome tuberculosis antigen card test detected antigens in our study population with approximately 97.48% sensitivity and 95.79% specificity. This is the first study to report the liposomal encapsulation of culture filtrate proteins from M. tuberculosis for diagnostic application. Copyright © 2015. Published by Elsevier B.V.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: management.

PubMed

Park, Dong Il; Hisamatsu, Tadakazu; Chen, Minhu; Ng, Siew Chien; Ooi, Choon Jin; Wei, Shu Chen; Banerjee, Rupa; Hilmi, Ida Normiha; Jeen, Yoon Tae; Han, Dong Soo; Kim, Hyo Jong; Ran, Zhihua; Wu, Kaichun; Qian, Jiaming; Hu, Pin-Jin; Matsuoka, Katsuyoshi; Andoh, Akira; Suzuki, Yasuo; Sugano, Kentaro; Watanabe, Mamoru; Hibi, Toshifumi; Puri, Amarender S; Yang, Suk-Kyun

2018-01-01

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised 3 parts: management of latent TB in preparation for anti-TNF therapy, monitoring during anti-TNF therapy, and management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

Evaluating the efficacy of tuberculosis Advocacy, Communication and Social Mobilization (ACSM) activities in Pakistan: a cross-sectional study.

PubMed

Turk, Tahir; Newton, Fiona J; Netwon, Joshua D; Naureen, Farah; Bokhari, Jodah

2013-09-25

Tuberculosis (TB) continues to be a major public health and development problem within many low- and middle-income countries. Although Advocacy, Communication and Social Mobilization (ACSM) activities have been undertaken in high TB burden countries to remediate these issues, there is little empirical evidence of the efficacy of these approaches. The purpose of this study was therefore to examine the efficacy of an ACSM program undertaken within Pakistan. Pakistan was chosen because it has received considerable funding for ACSM related activities and is one of 22 high-burden TB countries. The program was evaluated by surveying a stratified random sample of 2,400 participants across 57 districts of Pakistan. Participants were categorized into one of three groups: aware of both media and community ACSM activities (AwareMedia&Community), aware of ACSM media activities only (AwareMedia), or unaware of any ACSM activities (UnawareMedia&Community). Independent measures ANCOVA revealed complex differences in knowledge, attitudes, and intended behaviors towards TB between the three groups. In general, UnawareMedia&Community cases had a poorer understanding of TB and its treatment, whilst awareness of ACSM activities was highest among literate and urban dwelling Pakistanis. Preferred sources of TB information were also found to vary by gender, geographic location, and literacy. Whilst highlighting improvements in knowledge and attitudes toward TB, the results also provide invaluable insights into areas where further work needs to be done to address deficits in TB understanding, particularly among rural and illiterate Pakistanis. Equally important, the findings have implications for future TB ACSM initiatives in Pakistan in terms of leveraging the preferred media channels of key demographic segments and exploring the degree to which exposure to multiple channels of communication may have an additive effect on health knowledge.

Towards earlier inclusion of Children in Tuberculosis (TB) drugs trials: Consensus statements from an Expert Panel

PubMed Central

Nachman, Sharon; Ahmed, Amina; Amanullah, Farhana; Becerra, Mercedes C; Botgros, Radu; Brigden, Grania; Browning, Renee; Gardiner, Elizabeth; Hafner, Richard; Hesseling, Anneke; How, Cleotilde; Jean-Philippe, Patrick; Lessem, Erica; Makhene, Mamodikoe; Mbelle, Nontombi; Marais, Ben; McIlleron, Helen; Mc Neeley, David F; Mendel, Carl; Murray, Stephen; Navarro, Eileen; Oramasionwu, Gloria E; Porcalla, Ariel R; Powell, Clydette; Powell, Mair; Rigaud, Mona; Rouzier, Vanessa; Samson, Pearl; Schaaf, H. Simon; Shah, Seema; Starke, Jeff; Swaminathan, Soumya; Wobudeya, Eric; Worrell, Carol

2015-01-01

Children represent a significant proportion of the global tuberculosis (TB) burden, and may be disproportionately more affected by its most severe clinical manifestations. Currently available treatments for pediatric drug-susceptible (DS) and drug-resistant (DR) TB, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxicities, and an overall lack of suitable, child-friendly formulations. The complex and burdensome nature of administering the existing regimens to treat DS TB also contributes to the rise of DR TB strains. Despite the availability and use of these therapies for decades, a dearth of dosing evidence in children underscores the importance of sustained efforts for TB drug development to better meet the treatment needs of children with TB. Several new TB drugs and regimens with promising activity against both DS and DR TB strains have recently entered clinical development and are in various phases of clinical evaluation in adults or have received marketing authorization for adults. However, initiation of clinical trials to evaluate these drugs in children is often deferred, pending the availability of complete safety and efficacy data in adults or after drug approval. This document summarizes consensus statements from an international panel of childhood TB opinion leaders which support the initiation of evaluation of new TB drugs and regimens in children at earlier phases of the TB Drug development cycle. PMID:25957923

Agents of Change: The Role of Healthcare Workers in the Prevention of Nosocomial and Occupational Tuberculosis

PubMed Central

Nathavitharana, Ruvandhi R.; Bond, Patricia; Dramowski, Angela; Kotze, Koot; Lederer, Philip; Oxley, Ingrid; Peters, Jurgens A.; Rossouw, Chanel; van der Westhuizen, Helene-Mari; Willems, Bart; Ting, Tiong Xun; von Delft, Arne; von Delft, Dalene; Duarte, Raquel; Nardell, Edward; Zumla, Alimuddin

2018-01-01

Healthcare workers (HCWs) play a central role in global tuberculosis (TB) elimination efforts but their contributions are undermined by occupational TB. HCWs have higher rates of latent and active TB than the general population due to persistent occupational TB exposure, particularly in settings where there is a high prevalence of undiagnosed TB in healthcare facilities and TB infection control (TB-IC) programmes are absent or poorly implemented. Occupational health programmes in high TB burden settings are often weak or non-existent and thus data that record the extent of the increased risk of occupational TB globally are scarce. HCWs represent a limited resource in high TB burden settings and occupational TB can lead to workforce attrition. Stigma plays a role in delayed diagnosis, poor treatment outcomes and impaired wellbeing in HCWs who develop TB. Ensuring the prioritization and implementation of TB-IC interventions and occupational health programmes, which include robust monitoring and evaluation, is critical to reduce nosocomial TB transmission to patients and HCWs. The provision of preventive therapy for HCWs with latent TB infection can also prevent progression to active TB. Unlike other patient groups, HCWs are in a unique position to serve as agents of change to raise awareness, advocate for necessary resource allocation and implement TB-IC interventions, with appropriate support from dedicated TB-IC officers at the facility and national TB programme level. Students and community health workers (CHWs) must be engaged and involved in these efforts. Nosocomial TB transmission is an urgent public health problem and adopting rights-based approaches can be helpful. However, these efforts cannot succeed without increased political will, supportive legal frameworks and financial investments to support HCWs in efforts to decrease TB transmission. PMID:28256382

Agents of change: The role of healthcare workers in the prevention of nosocomial and occupational tuberculosis.

PubMed

Nathavitharana, Ruvandhi R; Bond, Patricia; Dramowski, Angela; Kotze, Koot; Lederer, Philip; Oxley, Ingrid; Peters, Jurgens A; Rossouw, Chanel; van der Westhuizen, Helene-Mari; Willems, Bart; Ting, Tiong Xun; von Delft, Arne; von Delft, Dalene; Duarte, Raquel; Nardell, Edward; Zumla, Alimuddin

2017-03-01

Healthcare workers (HCWs) play a central role in global tuberculosis (TB) elimination efforts but their contributions are undermined by occupational TB. HCWs have higher rates of latent and active TB than the general population due to persistent occupational TB exposure, particularly in settings where there is a high prevalence of undiagnosed TB in healthcare facilities and TB infection control (TB-IC) programmes are absent or poorly implemented. Occupational health programmes in high TB burden settings are often weak or non-existent and thus data that record the extent of the increased risk of occupational TB globally are scarce. HCWs represent a limited resource in high TB burden settings and occupational TB can lead to workforce attrition. Stigma plays a role in delayed diagnosis, poor treatment outcomes and impaired well-being in HCWs who develop TB. Ensuring the prioritization and implementation of TB-IC interventions and occupational health programmes, which include robust monitoring and evaluation, is critical to reduce nosocomial TB transmission to patients and HCWs. The provision of preventive therapy for HCWs with latent TB infection (LTBI) can also prevent progression to active TB. Unlike other patient groups, HCWs are in a unique position to serve as agents of change to raise awareness, advocate for necessary resource allocation and implement TB-IC interventions, with appropriate support from dedicated TB-IC officers at the facility and national TB programme level. Students and community health workers (CHWs) must be engaged and involved in these efforts. Nosocomial TB transmission is an urgent public health problem and adopting rights-based approaches can be helpful. However, these efforts cannot succeed without increased political will, supportive legal frameworks and financial investments to support HCWs in efforts to decrease TB transmission. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Leveraging tuberculosis case relative locations to enhance case detection and linkage to care in Swaziland.

PubMed

Brunetti, Marie; Rajasekharan, Sathyanath; Ustero, Piluca; Ngo, Katherine; Sikhondze, Welile; Mzileni, Buli; Mandalakas, Anna; Kay, Alexander W

2018-01-01

In Swaziland, as in many high HIV/TB burden settings, there is not information available regarding the household location of TB cases for identifying areas of increased TB incidence, limiting the development of targeted interventions. Data from "Butimba", a TB REACH active case finding project, was re-analyzed to provide insight into the location of TB cases surrounding Mbabane, Swaziland. The project aimed to identify geographical areas with high TB burdens to inform active case finding efforts. Butimba implemented household contact tracing; obtaining landmark based, informal directions, to index case homes, defined here as relative locations. The relative locations were matched to census enumeration areas (known location reference areas) using the Microsoft Excel Fuzzy Lookup function. Of 403 relative locations, an enumeration area reference was detected in 388 (96%). TB cases in each census enumeration area and the active case finders in each Tinkhundla, a local governmental region, were mapped using the geographic information system, QGIS 2.16. Urban Tinkhundla predictably accounted for most cases; however, after adjusting for population, the highest density of cases was found in rural Tinkhundla. There was no correlation between the number of active case finders currently assigned to the 7 Tinkhundla surrounding Mbabane and the total number of TB cases (Spearman rho = -0.57, p  = 0.17) or the population adjusted TB cases (Spearman rho = 0.14, p  = 0.75) per Tinkhundla. Reducing TB incidence in high-burden settings demands novel analytic approaches to study TB case locations. We demonstrated the feasibility of linking relative locations to more precise geographical areas, enabling data-driven guidance for National Tuberculosis Programs' resource allocation. In collaboration with the Swazi National Tuberculosis Control Program, this analysis highlighted opportunities to better align the active case finding national strategy with the TB disease burden.

[PULMONARY AND INTESTINAL TUBERCULOSIS DEVELOPING ACUTE TUBERCULOUS PERFORATION OF THE INTESTINE DURING ANTITUBERCULOSIS THERAPY].

PubMed

Saitou, Miwako; Suzuki, Tomoko; Niitsuma, Katsunao

2015-09-01

Intestinal tuberculosis (TB) was recognized as the most common complication with a high frequency of active pulmonary TB during the TB epidemic period. However, intestinal TB has become a rare disease, and intestinal perforation due to intestinal TB is extremely rare. We herein report two cases of tuberculous intestinal perforation. A 41-year-old man was admitted to our hospital complaining of persistent cough and anorexia. He was in poor nutritional condition, and his body mass index (BMI) and prognostic nutrition index (PNI) were 13.4 and 36.4, respectively. He was diagnosed with pulmonary TB and received anti-TB therapy. On the 51st day of hospitalization, he developed intestinal perforation. Pathologically caseating epithelioid granulomas were noted at the ulcer lesion. A 61-year-old man was admitted to our hospital due to miliary TB caused by intestinal TB. He had taken oral immunosuppressive drugs and steroids for dermatomyositis over the previous eight years and had a poor nutritional condition, with a BMI of 13.4 and a PNI of 14.4. While receiving anti-TB therapy, he developed intestinal perforation on the 97th day of hospitalization. The patient's poor nutritional condition and immune reconstitution may have contributed to the intestinal perforation.

Tuberculosis: Is the landscape changing?

PubMed

Khatua, Sutapa; Geltemeyer, Abby M; Gourishankar, Anand

2017-01-01

Robert Heinrich Herman Koch, a German physician and microbiologist, received Nobel Prize in 1905 for identifying the specific causative agent of tuberculosis (TB). During his time it was believed that TB was an inherited disease. However he was convinced that the disease was caused by a bacterium and was infectious, tested his postulates using guinea pigs, and found the causative agent to be slow growing mycobacterium tuberculosis. TB is the second most common cause of death from infectious diseases after HIV/AIDS. Drug-resistant TB poses serious challenge to effective management of TB worldwide. Multidrug-resistant TB accounted for about half a million new cases and over 200,000 deaths in 2013. Whole-genome sequencing (first done in 1998) technologies have provided new insight into the mechanism of drug resistance. For the first time in 50 y, new anti TB drugs have been developed. The World Health Organization (WHO) has recently revised their treatment guidelines based on 32 studies. In United States, latent TB affects between 10 and 15 million people, 10% of whom may develop active TB disease. QuantiFERON TB Gold and T-SPOT.TB test are used for diagnosis. Further research will look into the importance of newly discovered gene mutations in causing drug resistance.

Elevated Neopterin Levels Are Associated with Increased Tuberculosis Risk in Rheumatoid Arthritis Patients with QuantiFERON Conversion during Biologic Therapy

PubMed Central

Chen, Der-Yuan; Chen, Hsin-Hua; Hsieh, Chia-Wei; Yeh, Yea-Wen; Lan, Joung-Liang

2016-01-01

QuantiFERON-TB-Gold (QFT-G) conversion is frequently observed in rheumatoid arthritis (RA) patients receiving biologic therapy. However, there have not been any known biomarkers available for detecting tuberculosis (TB) in QFT-G converters. We aimed to evaluate clinical utility of cytokines/chemokines for detecting TB in patients with QFT-G conversion. Among a total of 227 RA patients who underwent QFT-G assay, 187 QFT-G-negative patients received biologic therapy without isoniazid prophylaxis. QFT-G assay was repeated at week 52 of biologic therapy or at the time of TB diagnosis. Levels of cytokines/chemokines were determined by magnetic bead array or ELISA in QFT-G converters and 12 non-RA patients with TB (non-RA TB). QFT-G conversion was found in 54 (28.9%) of 187 baseline QFT-G-negative patients, of which 7 (13.0%) developed active TB during the one-year follow-up period. Among the examined cytokines/chemokines, non-stimulated and TB-antigen-stimulated neopterin levels were significantly higher in RA patients who developed TB (RA-TB) (median, 24.5pg/ml and 23053pg/ml, respectively) and non-RA TB patients (12.2pg/ml and 9633pg/ml, respectively) compared with QFT-G converters without TB (3.0pg/ml and 2720pg/ml, respectively, both p<0.001). Rising levels of neopterin relative to baseline (non-stimulated levels, 4.4pg/ml vs. 24.5pg/ml; TB-antigen-stimulated levels, 1801pg/ml vs. 23053pg/ml) were observed in QFT-G converters who developed TB. A high proportion (85.7%) of QFT-G converters with high plasma neopterin levels developed TB during the one-year follow-up period. In conclusion, RA patients with QFT-G conversion during the period of biologic therapy should be carefully monitored for elevation of neopterin levels, which is associated with TB risk in QFT-G converters, particularly in TB-endemic areas. PMID:27861525

The effect of HIV coinfection, HAART and TB treatment on cytokine/chemokine responses to Mycobacterium tuberculosis (Mtb) antigens in active TB patients and latently Mtb infected individuals.

PubMed

Kassa, Desta; de Jager, Wilco; Gebremichael, Gebremedhin; Alemayehu, Yodit; Ran, Leonie; Fransen, Justin; Wolday, Dawit; Messele, Tsehaynesh; Tegbaru, Belete; Ottenhoff, Tom H M; van Baarle, Debbie

2016-01-01

Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-γ, IL-2, IL-17, IL-10, IP-10 and MIP-1α were measured in supernatants of whole blood stimulated with Mtb specific fusion protein ESAT-6/CFP-10 using xMAP technology. The study groups were HIV positive TB patients (HIV(+)TB(+)), HIV negative TB patients (HIV(-)TB(+)), HIV positive tuberculin skin test positive (TST+) (HIV(+)TST(+)), HIV negative TST+ (HIV(-)TST(+)), and HIV(-)TST(-) individuals. Compared to HIV(-)TST(-), latent TB infection led to increased levels of IP-10, IFN-γ and IL-17, while levels of IL-2 and IP-10 were increased with active TB. Levels of IFN-γ, IL-17, MIP-1α, and IL-10 were increased in HIV(-)TST(+) individuals compared to HIV(-)TB(+) patients. HIV coinfection decreased the level of IFN-γ, IL-17, IP-10 and IL-2. After six months (M6) of anti-TB treatment (ATT) in HIV(-)TB(+) patients, IFN-γ, IL-10, and MIP-1α levels normalized. After M6 and M18 of ATT plus HAART in HIV(+)TB(+) patients, levels of MIP-1α and IL-10 normalized, while this was not the case for IFN-γ, IL-2, IL-17, and IP-10 levels. In HIV(+)TST(+) patients on HAART, levels of IFN-γ, IL-17, IL-10 and MIP-1α normalized, while no change in the levels of IL-2 and IP-10 were observed. In conclusion, the simultaneous measurement of IFN-γ, IL-17 and IP-10 may assist in diagnosing LTBI; IL-2 and IP-10 may assist in diagnosing active TB; while IFN-γ, IL-17, MIP-1α, and IL-10 levels could help to discriminate LTBI and active TB. In addition, IL-10 and MIP-1α levels could help to monitor responses to TB treatment and HAART. Copyright © 2015 Elsevier Ltd. All rights reserved.

Characterization of Plasmodium vivax Transmission-Blocking Activity in Low to Moderate Malaria Transmission Settings of the Colombian Pacific Coast

PubMed Central

Arévalo-Herrera, Myriam; Solarte, Yezid; Rocha, Leonardo; Álvarez, Diego; Beier, John C.; Herrera, Sócrates

2011-01-01

Malaria infection induces antibodies capable of suppressing the infectivity of gametocytes and gametes, however, little is known about the duration of the antibody response, the parasite specificity, and the role of complement. We report the analyses of the transmission-blocking (TB) activity of sera collected from 105 Plasmodium vivax-infected and 44 non-infected individuals from a malaria endemic region of Colombia, using a membrane feeding assay in Anopheles albimanus mosquitoes. In infected donors we found that TB activity was antibody dose dependent (35%), lasted for 2–4 months after infection, and in 70% of the cases different P. vivax wild isolates displayed differential susceptibility to blocking antibodies. Additionally, in a number of assays TB was complement-dependent. Twenty-seven percent of non-infected individuals presented TB activity that correlated with antibody titers. Studies here provide preliminary data on factors of great importance for further work on the development of TB vaccines. PMID:21292881

Latent tuberculosis infections in hard-to-reach drug using population-detection, prevention and control.

PubMed

Hwang, Lu-Yu; Grimes, Carolyn Z; Beasley, R Palmer; Graviss, Edward A

2009-12-01

Interferon-gamma release assays (IGRAs) need be evaluated for effectiveness as screening tests for tuberculosis (TB) infection in drug users. These tests have demonstrated improved sensitivity and specificity, but have not been studied in drug users. These one step blood tests are intended to replace the tuberculin skin test (TST), which is difficult to use and requires 48 hour follow-up, so they are expected to be particularly suitable for risk groups, like drug users, in whom follow-up is problematic. Drug users have traditionally been identified as being at increased risk for acquiring TB disease. The results of our pilot study using the TST and simpler and more sensitive interferon-gamma release assays showed that about 45% of current drug users in Houston tested have at least one test positive for latent tuberculosis infection (LTBI). These preliminary data suggest that there is an important reservoir of LTBI in drug using populations, and the risk of progression to active TB disease with other infections is great. However, LTBI in drug using populations has not been studied in depth and deserves further investigation. We need to evaluate the validity of IGRAs for detection of latent TB infection, the factors associated with LTBI, the incidence and risk for developing active TB disease in drug users and the effectiveness of early treatment of LTBI. We believe that using better tuberculosis screening tools will allow us to more accurately measure the prevalence of latent TB infection and incidence of active TB disease in drug using populations and develop more effective TB prevention and treatment interventions in the community.

Detection of circulating Mycobacterium tuberculosis-specific DNA by droplet digital PCR for vaccine evaluation in challenged monkeys and TB diagnosis.

PubMed

Song, Neng; Tan, Yang; Zhang, Lingyun; Luo, Wei; Guan, Qing; Yan, Ming-Zhe; Zuo, Ruiqi; Liu, Weixiang; Luo, Feng-Ling; Zhang, Xiao-Lian

2018-04-24

Mycobacterium tuberculosis (M. tb) is emerging as a more serious pathogen due to the increased multidrug-resistant TB and co-infection of human immunodeficiency virus (HIV). The development of an effective and sensitive detection method is urgently needed for bacterial load evaluation in vaccine development, early TB diagnosis, and TB treatment. Droplet digital polymerase chain reaction (ddPCR) is a newly developed sensitive PCR method for the absolute quantification of nucleic acid concentrations. Here, we used ddPCR to quantify the circulating virulent M. tb-specific CFP10 (10-kDa culture filtrate protein, Rv3874) and Rv1768 DNA copy numbers in the blood samples from Bacille Calmette-Guerin (BCG)-vaccinated and/or virulent M. tb H37Rv-challenged rhesus monkeys. We found that ddPCR was more sensitive compared to real-time fluorescence quantitative PCR (qPCR), as the detection limits of CFP10 were 1.2 copies/μl for ddPCR, but 15.8 copies/μl for qPCR. We demonstrated that ddPCR could detect CFP10 and Rv1768 DNA after 3 weeks of infection and at least two weeks earlier than qPCR in M.tb H37Rv-challenged rhesus monkey models. DdPCR could also successfully quantify CFP10 and Rv1768 DNA copy numbers in clinical TB patients' blood samples (active pulmonary TB, extrapulmonary TB (EPTB), and infant TB). To our knowledge, this study is the first to demonstrate that ddPCR is an effective and sensitive method of measuring the circulating CFP10 and Rv1768 DNA for vaccine development, bacterial load evaluation in vivo, and early TB (including EPTB and infant TB) diagnosis as well.

Patterns of funding allocation for tuberculosis control in fragile states.

PubMed

Warsame, A; Patel, P; Checchi, F

2014-01-01

To assess recent (2006-2010) tuberculosis (TB) funding patterns in conflict and non-conflict-affected fragile states to inform global policy. The Creditor Reporting System was analysed for official development assistance funding disbursements towards TB control in 11 conflict-affected states, 17 non-conflict-affected fragile states and 38 comparable non-fragile states. The amounts of funding, funding relative to burden, funding relative to malaria and human immunodeficiency virus (HIV) control, disbursements relative to commitments, sources of funding as well as funding activities were extracted and analysed. Fragile states received on average more per capita for TB control relative to non-fragile states (US0.159 vs. US0.079). However conflict-affected fragile states received on average less per capita than non-conflict-affected states (US0.144 vs. US0.203), despite worse development indicators. Conflict-affected fragile states also received on average only 70% of TB funds already committed. Analysis by burden revealed the least disparity in funding in highest prevalence settings. Analysis of funding activities suggests increasing importance of TB-HIV integration, multidrug-resistant TB and research in both fragile and non-fragile states. Relative to non-conflict-affected fragile states, conflict-affected fragile states received approximately two thirds the per capita funding for TB. This study revealed disparities in TB control funding between fragile and non-fragile as well as between conflict and non-conflict-affected fragile states. Findings suggest possible avenues for improving the allocation of global TB funding.

Determination of dehydroepiandrosterone and its biologically active oxygenated metabolites in human plasma evinces a hormonal imbalance during HIV-TB coinfection.

PubMed

Vecchione, María Belén; Eiras, Javier; Suarez, Guadalupe Verónica; Angerami, Matías Tomás; Marquez, Cecilia; Sued, Omar; Ben, Graciela; Pérez, Héctor Miguel; Gonzalez, Diego; Maidana, Patricia; Mesch, Viviana; Quiroga, María Florencia; Bruttomesso, Andrea Claudia

2018-04-27

An estimated one third of the world's population is affected by latent tuberculosis (TB), which once active represents a leading cause of death among infectious diseases. Human immunodeficiency virus (HIV) infection is a main predisposing factor to TB reactivation. Individuals HIV-TB co-infected develop a chronic state of inflammation associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This results in a hormonal imbalance, disturbing the physiological levels of cortisol and dehydroepiandrosterone (DHEA). DHEA and its oxygenated metabolites androstenediol (AED), androstenetriol (AET) and 7-oxo-DHEA are immunomodulatory compounds that may regulate physiopathology in HIV-TB co-infection. In order to study possible changes in plasma levels of these hormones, we developed an approach based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). To our knowledge, this represents the first report of their simultaneous measurement in HIV-TB individuals and the comparison with healthy donors, obtaining statistically higher plasma levels of DHEA, AET and 7-oxo-DHEA in patients. Moreover, we found that concentrations of 7-oxo-DHEA positively correlated with absolute CD4+ T cell counts, nadir CD4+ T cell values and with individuals who presented TB restricted to the lungs. This research contributes to understanding the role of these hormones in HIV-TB and emphasizes the importance of deepening their study in this context.

[Development of antituberculous drugs: current status and future prospects].

PubMed

Tomioka, Haruaki; Namba, Kenji

2006-12-01

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The authors reviewed (1) the history and present status of chemical genomics that is defined as the systemic search for a selective small molecular modulator for each function of all gene products, (2) recent studies of the authors on profiles of the interactions between various kinds of human proteins and small molecule modulators using the new technology devised by Reverse Proteomics Research Institute, and (3) future prospects of the development of new antituberculous drugs based on chemical genomics. 3. It appears also promising to develop new types of drug administration systems using drug vehicles, which enable efficacious drug delivery to their target in vivo. Dr. Izumikawa, Dr. Ohno and Dr. Kohno reviewed the usefulness of liposome- and polymer-based technologies, which enable efficacious delivery of encapsulated drugs at required doses for prolonged periods of time with only a single shot without toxicity, and also enable highly targeted delivery of drugs to their target in vivo. They indicated that the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better clinical outcome. 4. Immunoadjunctive therapy appears to be promising in improving outcome of clinical control of refractory mycobacterial infections, including MDR-TB and M. avium complex infection. Dr. Shimizu, Dr. Sato and Dr. Tomioka reviewed the present status of immunotherapy of mycobacterial infections in combination with antimycobacterial drugs. They indicated that the development of new classes of immunomodulators other than cytokines (IL-2, IFN-gamma, GM-CSF, IL-12, etc.) particularly those with no severe side-effects, are urgently needed. Their review dealed with some promising immunoadjunctive agents, especially ATP and its analogues, which potentiate macrophage antimycobacterial activity via purinergic P2 receptors. The aim of this symposium is to address the future prospects of the development of new drugs and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED)

Activation and inhibition of CTP synthase from Trypanosoma brucei, the causative agent of African sleeping sickness.

PubMed

Steeves, Craig H; Bearne, Stephen L

2011-09-15

CTP Synthase from Trypanosoma brucei (TbCTPS) catalyzes the conversion of UTP to CTP and is a recognized target for the development of antiprotozoal agents. GTP activates glutamine-dependent CTP formation catalyzed by TbCTPS at concentrations below 0.2 mM, but inhibits this activity at concentrations above 0.2 mM. TbCTPS catalyzes ammonia-dependent CTP formation, which is inhibited by purine derivatives such as GTP, guanosine, caffeine, and uric acid with IC(50) values of 460, 380, 480, and 100 μM, respectively. These observations suggest that the purine ring may serve as a useful scaffold for the development of inhibitors of trypanosomal CTP synthase. Copyright © 2011 Elsevier Ltd. All rights reserved.

T-SPOT.TB in Detection of Active Tuberculosis During Pregnancy: A Retrospective Study in China.

PubMed

Chen, Qiaopei; Guo, Xuxiao; Wang, Xinfeng; Wang, Maoshui

2016-01-06

Interferon-gamma release assays have not been validated in active TB among pregnant women. Therefore, the objective of this retrospective study was to estimate the diagnostic value of T-SPOT.TB in active TB among pregnant women. Between May 2012 and May 2015, 26 consecutive pregnant women with suspected TB were enrolled in our study. The clinicopathological characteristics and T-SPOT.TB results were reviewed and analyzed. Pregnant patients were divided into a TB group (n=21) and a Non-TB group (n=5). In the TB group, 5 patients had pulmonary TB, 5 had pulmonary TB+ extrapulmonary TB, and 11 had exclusively extrapulmonary TB. The most common site of extrapulmonary TB was pleural (n=11). Statistical analysis showed that the lymphocyte count in the TB group was lower than in the Non-TB group (P<0.05). For detection of active TB during pregnancy, T-SPOT.TB had a high sensitivity of 100.0% (84.5%-100.0%) and a specificity of 80.0% (37.6-96.4%). T-SPOT.TB shows good performance in detection of active tuberculosis during pregnancy. Interferon gamma release assay for TB screening of pregnant women is recommended in clinical practice because it may be a more appropriate diagnostic tool than the tuberculin skin test.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: Management.

PubMed

Park, Dong Il; Hisamatsu, Tadakazu; Chen, Minhu; Ng, Siew Chien; Ooi, Choon Jin; Wei, Shu Chen; Banerjee, Rupa; Hilmi, Ida Normiha; Jeen, Yoon Tae; Han, Dong Soo; Kim, Hyo Jong; Ran, Zhihua; Wu, Kaichun; Qian, Jiaming; Hu, Pin-Jin; Matsuoka, Katsuyoshi; Andoh, Akira; Suzuki, Yasuo; Sugano, Kentaro; Watanabe, Mamoru; Hibi, Toshifumi; Puri, Amarender S; Yang, Suk-Kyun

2018-01-01

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised three parts: (3) management of latent TB in preparation for anti-TNF therapy, (4) monitoring during anti-TNF therapy, and (5) management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Evaluation of a TB infection control implementation initiative in out-patient HIV clinics in Zambia and Botswana.

PubMed

Emerson, C; Lipke, V; Kapata, N; Mwananyambe, N; Mwinga, A; Garekwe, M; Lanje, S; Moshe, Y; Pals, S L; Nakashima, A K; Miller, B

2016-07-01

Out-patient human immunodeficiency virus (HIV) care and treatment clinics in Zambia and Botswana, countries with a high burden of HIV and TB infection. To develop a tuberculosis infection control (TB IC) training and implementation package and evaluate the implementation of TB IC activities in facilities implementing the package. Prospective program evaluation of a TB IC training and implementation package using a standardized facility risk assessment tool, qualitative interviews with facility health care workers and measures of pre- and post-test performance. A composite measure of facility performance in TB IC improved from 32% at baseline to 50% at 1 year among eight facilities in Zambia, and from 27% to 80% at 6 months among 10 facilities in Botswana. Although there was marked improvement in indicators of managerial, administrative and environmental controls, key ongoing challenges remained in ensuring access to personal protective equipment and implementing TB screening in health care workers. TB IC activities at out-patient HIV clinics in Zambia and Botswana improved after training using the implementation package. Continued infrastructure support, as well as monitoring and evaluation, are needed to support the scale-up and sustainability of TB IC programs in facilities in low-resource countries.

Demographic predictors of active tuberculosis in people migrating to British Columbia, Canada: a retrospective cohort study.

PubMed

Ronald, Lisa A; Campbell, Jonathon R; Balshaw, Robert F; Romanowski, Kamila; Roth, David Z; Marra, Fawziah; Cook, Victoria J; Johnston, James C

2018-02-26

Canadian tuberculosis (TB) guidelines recommend targeting postlanding screening for and treatment of latent tuberculosis infection (LTBI) in people migrating to Canada who are at increased risk for TB reactivation. Our objectives were to calculate robust longitudinal estimates of TB incidence in a cohort of people migrating to British Columbia, Canada, over a 29-year period, and to identify groups at highest risk of developing TB based on demographic characteristics at time of landing. We included all individuals ( n = 1 080 908) who became permanent residents of Canada between Jan. 1, 1985, and Dec. 31, 2012, and were resident in BC at any time between 1985 and 2013. Multiple administrative databases were linked to the provincial TB registry. We used recursive partitioning models to identify populations with high TB yield. Active TB was diagnosed in 2814 individuals (incidence rate 24.2/100 000 person-years). Demographic factors (live-in caregiver, family, refugee immigration classes; higher TB incidence in country of birth; and older age) were strong predictors of TB incidence in BC, with elevated rates continuing many years after entry into the cohort. Recursive partitioning identified refugees 18-64 years of age from countries with a TB incidence greater than 224/100 000 population as a high-yield group, with 1% developing TB within the first 10 years. These findings support recommendations in Canadian guidelines to target postlanding screening for and treatment of LTBI in adult refugees from high-incidence countries. Because high-yield populations can be identified at entry via demographic data, screening at this point may be practical and high-impact, particularly if the LTBI care cascade can be optimized. © 2018 Joule Inc. or its licensors.

Demographic predictors of active tuberculosis in people migrating to British Columbia, Canada: a retrospective cohort study

PubMed Central

Ronald, Lisa A.; Campbell, Jonathon R.; Balshaw, Robert F.; Romanowski, Kamila; Roth, David Z.; Marra, Fawziah; Cook, Victoria J.; Johnston, James C.

2018-01-01

BACKGROUND: Canadian tuberculosis (TB) guidelines recommend targeting postlanding screening for and treatment of latent tuberculosis infection (LTBI) in people migrating to Canada who are at increased risk for TB reactivation. Our objectives were to calculate robust longitudinal estimates of TB incidence in a cohort of people migrating to British Columbia, Canada, over a 29-year period, and to identify groups at highest risk of developing TB based on demographic characteristics at time of landing. METHODS: We included all individuals (n = 1 080 908) who became permanent residents of Canada between Jan. 1, 1985, and Dec. 31, 2012, and were resident in BC at any time between 1985 and 2013. Multiple administrative databases were linked to the provincial TB registry. We used recursive partitioning models to identify populations with high TB yield. RESULTS: Active TB was diagnosed in 2814 individuals (incidence rate 24.2/100 000 person-years). Demographic factors (live-in caregiver, family, refugee immigration classes; higher TB incidence in country of birth; and older age) were strong predictors of TB incidence in BC, with elevated rates continuing many years after entry into the cohort. Recursive partitioning identified refugees 18–64 years of age from countries with a TB incidence greater than 224/100 000 population as a high-yield group, with 1% developing TB within the first 10 years. INTERPRETATION: These findings support recommendations in Canadian guidelines to target postlanding screening for and treatment of LTBI in adult refugees from high-incidence countries. Because high-yield populations can be identified at entry via demographic data, screening at this point may be practical and high-impact, particularly if the LTBI care cascade can be optimized. PMID:29483329

Cellular Architecture of Spinal Granulomas and the Immunological Response in Tuberculosis Patients Coinfected with HIV.

PubMed

Bhattacharya, Debapriya; Danaviah, Siva; Muema, Daniel M; Akilimali, Ngomu Akeem; Moodley, Prashini; Ndung'u, Thumbi; Das, Gobardhan

2017-01-01

Mycobacterium tuberculosis ( M.tb ) and HIV are individually responsible for the most deaths worldwide among all infectious agents, and coinfection with M.tb and HIV is a significant public health challenge in the developing world. Although the lung is the primary target organ for tuberculosis (TB), M.tb can also cause extrapulmonary tuberculosis (EPTB) such as in the bones and joints. Treatment of EPTB is much more challenging than treatment of pulmonary TB. The hallmark of the host immune response against TB is the formation of organized structures called granulomas that are infiltrated with immune cells and are rich in cytokines and chemokines. Inside granulomas, the host confines the M.tb bacteria to a particular region of the organ and avoids dispersion. In this study, we analyzed immune cells in bone granulomas of patients with EPTB that are also coinfected with HIV. We found that HIV-infected TB patients have dispersed bone granulomas, with reduced T cell numbers and a concomitant increase in plasma cells. Additionally, HIV-infected patients exhibited dramatically increased serum levels of IgM and IgG1 antibodies, which is indicative of T-cell-independent B-cell activation and mucosal T-cell activation, respectively. Interestingly, we also observed that CD29 + stem cells are increased in HIV-TB coinfection, suggesting a link with HIV infection. Therefore, our work provides new insights into the architecture of spinal TB granulomas and the role of B-cells and humoral immunity against a highly infectious intracellular pathogen. We propose that our findings will inform biomarker identification for EPTB and possibly the development of related therapeutics and/or vaccines to protect HIV-infected patients against disseminated TB.

Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis.

PubMed

De Groote, Mary A; Sterling, David G; Hraha, Thomas; Russell, Theresa M; Green, Louis S; Wall, Kirsten; Kraemer, Stephan; Ostroff, Rachel; Janjic, Nebojsa; Ochsner, Urs A

2017-10-01

New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up. HIV coinfection was present in 34% of samples, and 25% were sputum smear negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naive Bayes classifier using six host response markers (HR6 model), including SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C, performed well in a training set (area under the sensitivity-specificity curve [AUC] of 0.94) and in a blinded verification set (AUC of 0.92) to distinguish TB and non-TB samples. Differential expression was also highly significant ( P < 10 -20 ) for previously described TB markers, such as IP-10, LBP, FCG3B, and TSP4, and for many novel proteins not previously associated with TB. Proteins with the largest median fold changes were SAA (serum amyloid protein A), NPS-PLA2 (secreted phospholipase A2), and CA6 (carbonic anhydrase 6). Target product profiles (TPPs) for a non-sputum biomarker test to diagnose active TB for treatment initiation (TPP#1) and for a community-based triage or referral test (TPP#2) have been published by the WHO. With 90% sensitivity and 80% specificity, the HR6 model fell short of TPP#1 but reached TPP#2 performance criteria. In conclusion, we identified and validated a six-marker signature for active TB that warrants diagnostic development on a patient-near platform. Copyright © 2017 De Groote et al.

Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis

PubMed Central

De Groote, Mary A.; Sterling, David G.; Hraha, Thomas; Russell, Theresa M.; Green, Louis S.; Wall, Kirsten; Kraemer, Stephan; Ostroff, Rachel; Janjic, Nebojsa

2017-01-01

ABSTRACT New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up. HIV coinfection was present in 34% of samples, and 25% were sputum smear negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naive Bayes classifier using six host response markers (HR6 model), including SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C, performed well in a training set (area under the sensitivity-specificity curve [AUC] of 0.94) and in a blinded verification set (AUC of 0.92) to distinguish TB and non-TB samples. Differential expression was also highly significant (P < 10−20) for previously described TB markers, such as IP-10, LBP, FCG3B, and TSP4, and for many novel proteins not previously associated with TB. Proteins with the largest median fold changes were SAA (serum amyloid protein A), NPS-PLA2 (secreted phospholipase A2), and CA6 (carbonic anhydrase 6). Target product profiles (TPPs) for a non-sputum biomarker test to diagnose active TB for treatment initiation (TPP#1) and for a community-based triage or referral test (TPP#2) have been published by the WHO. With 90% sensitivity and 80% specificity, the HR6 model fell short of TPP#1 but reached TPP#2 performance criteria. In conclusion, we identified and validated a six-marker signature for active TB that warrants diagnostic development on a patient-near platform. PMID:28794177

Development of Diazaquinomycin Class Antibiotics for the Treatment of Drug-Resistant TB Infections

DTIC Science & Technology

2016-10-01

exhibited weak antibacterial activity by targeting thymidylate synthase, though no reports of their anti-TB activity existed and our studies have suggested...Murphy, B. T. Diaza-anthracene antibiotics from a freshwater-derived actinomycete with selective antibacterial activity toward M. tuberculosis. ACS Inf...freshwater-derived actinomycete with selective antibacterial activity toward M. tuberculosis. ACS Infectious Diseases, 2015. 1: p. 168-174. (17) Mullowney

Tuberculosis in the workplace: developing partnerships with the garment industries in Bangladesh.

PubMed

Zafar Ullah, A N; Huque, R; Husain, A; Akter, S; Akter, H; Newell, J N

2012-12-01

To implement and evaluate a public-private partnership model involving garment factories to reduce the tuberculosis (TB) burden in this workforce. We used operational research to develop and evaluate a mechanism for effective and sustainable TB control in workplaces in three areas of Dhaka, Bangladesh. Strategies, protocols, guides and tools were developed with stakeholders. We assessed the impact of the project using quantitative and qualitative measures: changes in TB outcomes were calculated using standard indicators based on factory and DOTS centre records; changes in TB care-seeking behaviour were assessed using qualitative in-depth interviews with factory managers and medical personnel, and focus group discussions with factory workers, including TB patients. The project brought positive changes in knowledge, attitudes and practices of managers, workers and health care providers on TB care and control. During 2008-2010, a total of 3372 workers from a workforce of 69,000 were referred for sputum microscopy and 598 were diagnosed with smear-positive TB, 145 of whom received care at their workplace. The overall treatment success rate was 100%. It is feasible to engage factories in TB control activities in Bangladesh, and thereby increase case notifications and improve treatment outcomes.

Effectiveness of TB sensitization initiatives in improving the involvement of self help group members in rural TB control in south India.

PubMed

Thomas, Beena; Priscilla Rebecca, B; Dhanalakshmi, A; Rani, S; Deepa Lakshmi, A; Watson, Basilea; Vijayalakshmi, R; Muniyandi, M; Karikalan, N

2016-12-01

The 'End TB strategy' has highlighted the importance of inter-sectoral collaboration and community mobilization for achieving zero TB deaths by 2020. The aim of the study was to develop and test a model TB sensitization programme involving self help groups (SHGs). This experimental study was conducted in two blocks (intervention and control), in Tiruvallur district. The intervention content included short-lecture, musical story telling activity, role play, short film on TB. The impact was compared at baseline, third and sixth months in terms of SHGs' awareness, promotion of awareness, identification and referral of presumptive TB cases and provision of TB treatment. A total of 764 vs 796 SHGs were enrolled in control and intervention groups, respectively. The knowledge attitude, and practice score (lower score indicated a better attitude and practice), from baseline to 6 months was significantly reduced (29 to 24) in the intervention group. Similarly, a significant difference was observed in identification and referral of chest symptomatics in the intervention group at 3 and 6 months. During the 3 month follow-up a significantly higher proportion of SHG members were involved in TB awareness activities in the intervention (623/748 [83.3%]) vs control group (471/728 [64.7%]; p<0.001). Findings from this study highlight the feasibility of involving SHGs through a model TB sensitization program for strengthening TB prevention and control activities. © The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Treatment of Latent Tuberculosis Infection.

PubMed

Tang, Patrick; Johnston, James

2017-01-01

The treatment of latent tuberculosis infection (LTBI) is an essential component of tuberculosis (TB) elimination in regions that have a low incidence of TB. However, the decision to treat individuals with LTBI must consider the limitations of current diagnostic tests for LTBI, the risk of developing active TB disease, the potential adverse effects from chemoprophylactic therapy, and the importance of treatment adherence. When an individual has been diagnosed with LTBI and active TB has been ruled out, this is followed by an evaluation of the risks and benefits of LTBI treatment within the context of the regional epidemiology of TB and public health priorities. Once the decision to treat LTBI has been reached, and the infection is not suspected to be due to drug-resistant TB, the recommended regimens include isoniazid and/or rifamycin-derivatives, and the choice of regimen will depend upon the clinical considerations for that individual, such as patient preference, concomitant medications, hepatic disease, pregnancy, or immunodeficiency. As the duration of treatment of LTBI therapy is many months, therapy must be offered within a plan that monitors for adverse drug reactions and emphasizes adherence. For latent multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB) infection, the management is more complicated as there are few options for chemoprophylactic therapy and little evidence regarding the efficacy or risks of these regimens.

Risk factors for mortality among HIV-positive patients with and without active tuberculosis in Dar es Salaam, Tanzania.

PubMed

Mugusi, Sabina F; Ngaimisi, Eliford; Janabi, Mohamed Y; Mugusi, Ferdinand M; Minzi, Omary M S; Sasi, Philip G; Bakari, Muhammad; Lindquist, Lars; Aklillu, Eleni; Sandstrom, Eric G

2012-01-01

The aim of this study was to describe risk factors for mortality and clinical characteristics of HIV-infected patients with and without tuberculosis (TB) coinfection. A cohort of HIV-infected patients with CD4(+) T-cell counts of ≤200 cells/μl was recruited, consisting of 255 HIV-infected patients without active TB and 231 patients with active TB. All received a well-supervised treatment with an efavirenz-based HAART, and those coinfected with TB received appropriate anti-TB treatment. They were followed up for 48 weeks after HAART initiation. Common presenting symptoms in HIV-only patients were fever (36.5%), headache (34.5%), skin rash (34.5%) and weight loss (32%), while in HIV-TB patients the symptoms were weight loss (58%), cough (57.6%), night sweats (44.6%) and fever (34.2%). HIV-TB patients had significantly lower body mass index, Karnofsky scores and haemoglobin levels compared to those infected with HIV only, despite similar baseline CD4(+) T-cell counts. Overall, 12 (4.7%) HIV patients developed TB and 7 (3%) HIV-TB patients had worsening of their TB symptoms during the study period. Mortality was similar in the two groups, being 10.9% (16 deaths per 100 person years) and 11.3% (17 deaths per 100 person years) in HIV-only and HIV-TB patients, respectively. Overall, more males (13.1%) died compared to females (9.6%). Predictors of mortality were presence of oral candidiasis, Kaposi's sarcoma, low Karnofsky score, and low baseline white blood cell and CD4(+) T-cell counts. The outcomes following well-supervised treatment of HIV-TB patients are similar to those in patients with HIV alone. Predictors of mortality were those of advanced disease.

One of the possible mechanisms for the inhibition effect of Tb(III) on peroxidase activity in horseradish (Armoracia rusticana) treated with Tb(III).

PubMed

Guo, Shaofen; Cao, Rui; Lu, Aihua; Zhou, Qing; Lu, Tianhong; Ding, Xiaolan; Li, Chaojun; Huang, Xiaohua

2008-05-01

One of the possible mechanisms for the inhibition effect of Tb(III) on peroxidase activity in horseradish (Armoracia rusticana) treated with Tb(III) was investigated using some biophysical and biochemical methods. Firstly, it was found that a large amount of Tb(III) can be distributed on the cell wall, that some Tb(III) can enter into the horseradish cell, indicating that peroxidase was mainly distributed on cell wall, and thus that Tb(III) would interact with horseradish peroxidase (HRP) in the plant. In addition, peroxidase bioactivity was decreased in the presence of Tb(III). Secondly, a new peroxidase-containing Tb(III) complex (Tb-HRP) was obtained from horseradish after treatment with Tb(III); the molecular mass of Tb-HRP is near 44 kDa and the pI is about 8.80. Thirdly, the electrocatalytic activity of Tb-HRP is much lower than that of HRP obtained from horseradish without treatment with Tb(III). The decrease in the activity of Tb-HRP is due to the destruction (unfolding) of the conformation in Tb-HRP. The planarity of the heme active center in the Tb-HRP molecule was increased and the extent of exposure of Fe(III) in heme was decreased, leading to inhibition of the electron transfer. The microstructure change in Tb-HRP might be the result of the inhibition effect of Tb(III) on peroxidase activity in horseradish.

OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis In Vitro and In Mice

PubMed Central

Matsumoto, Makoto; Hashizume, Hiroyuki; Tomishige, Tatsuo; Kawasaki, Masanori; Tsubouchi, Hidetsugu; Sasaki, Hirofumi; Shimokawa, Yoshihiko; Komatsu, Makoto

2006-01-01

Background Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment. Methods and Findings Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006–0.024 μg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 μg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 μg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes. Conclusions We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment. PMID:17132069

OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.

PubMed

Matsumoto, Makoto; Hashizume, Hiroyuki; Tomishige, Tatsuo; Kawasaki, Masanori; Tsubouchi, Hidetsugu; Sasaki, Hirofumi; Shimokawa, Yoshihiko; Komatsu, Makoto

2006-11-01

Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment. Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006-0.024 microg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 microg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 microg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes. We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.

Evaluating the efficacy of tuberculosis Advocacy, Communication and Social Mobilization (ACSM) activities in Pakistan: a cross-sectional study

PubMed Central

2013-01-01

Background Tuberculosis (TB) continues to be a major public health and development problem within many low- and middle-income countries. Although Advocacy, Communication and Social Mobilization (ACSM) activities have been undertaken in high TB burden countries to remediate these issues, there is little empirical evidence of the efficacy of these approaches. The purpose of this study was therefore to examine the efficacy of an ACSM program undertaken within Pakistan. Pakistan was chosen because it has received considerable funding for ACSM related activities and is one of 22 high-burden TB countries. Methods The program was evaluated by surveying a stratified random sample of 2,400 participants across 57 districts of Pakistan. Participants were categorized into one of three groups: aware of both media and community ACSM activities (AwareMedia&Community), aware of ACSM media activities only (AwareMedia), or unaware of any ACSM activities (UnawareMedia&Community). Results Independent measures ANCOVA revealed complex differences in knowledge, attitudes, and intended behaviors towards TB between the three groups. In general, UnawareMedia&Community cases had a poorer understanding of TB and its treatment, whilst awareness of ACSM activities was highest among literate and urban dwelling Pakistanis. Preferred sources of TB information were also found to vary by gender, geographic location, and literacy. Conclusions Whilst highlighting improvements in knowledge and attitudes toward TB, the results also provide invaluable insights into areas where further work needs to be done to address deficits in TB understanding, particularly among rural and illiterate Pakistanis. Equally important, the findings have implications for future TB ACSM initiatives in Pakistan in terms of leveraging the preferred media channels of key demographic segments and exploring the degree to which exposure to multiple channels of communication may have an additive effect on health knowledge. PMID:24295034

Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans

PubMed Central

Velez, Digna Rosa; Wejse, Christian; Stryjewski, Martin E.; Abbate, Eduardo; Hulme, William F.; Myers, Jamie L.; Estevan, Rosa; Patillo, Sara G.; Olesen, Rikke; Tacconelli, Alessandra; Sirugo, Giorgio; Gilbert, John R.; Hamilton, Carol D.; Scott, William K.

2010-01-01

Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide in 2005. Approximately, 10% of infected individuals develop pulmonary or extrapulmonary TB, suggesting that host defense factors influence development of active disease. Toll-like receptor’ (TLR) polymorphisms have been associated with regulation of TLR expression and development of active TB. In the present study, 71 polymorphisms in TLR1, TLR2, TLR4, TLR6, and TLR9 were examined from 474 (295 cases and 179 controls) African-Americans, 381 (237 cases and 144 controls) Caucasians, and from 667 (321 cases and 346 controls) Africans from Guinea-Bissau for association with pulmonary TB using generalized estimating equations and logistic regression. Statistically significant associations were observed across populations at TLR9 and TLR2. The strongest evidence for association came at an insertion (I)/deletion (D) polymorphism (−196 to −174) in TLR2 that associated with TB in both Caucasians (II vs. ID&DD, OR=0.41 [95% CI 0.24–0.68], p=0.0007) and Africans (II vs. ID&DD, OR=0.70 [95% CI 0.51–0.95], p=0.023). Our findings in three independent population samples indicate that variations in TLR2 and TLR9 might play important roles in determining susceptibility to TB. PMID:19771452

Framework of behavioral indicators evaluating TB health promotion outcomes: a modified Delphi study of TB policymakers and health workers.

PubMed

Li, Ying; Ehiri, John; Hu, Daiyu; Oren, Eyal; Cao, Jia

2015-12-15

Although TB health promotion directed at policy makers and healthcare workers (HCWs) is considered important to tuberculosis (TB) control, no indicators currently assess the impact of such promotional activities. This article is the second in a series of papers that seek to establish a framework of behavioral indicators for outcome evaluation of TB health promotion, using the Delphi method. In the first article, we sought to establish a framework of behavioral indicators for outcome evaluation of TB health promotion among TB suspects and patients. The objective of this second article is to present an indicator framework that can be used to assess behavioral outcomes of TB health promotion directed at policy makers and HCWs. A two-round, modified Delphi method was used to establish the indicators. Sixteen experts who were knowledgeable and experienced in the field of TB control were consulted in Delphi surveys. A questionnaire was developed following 4 steps, and involved ranking indicators on a five-point Likert scale. The consensus level was 70 %. Median, mode, and Coefficient of variation (CV) were used to describe expert responses. An authority coefficient (Cr) was used to assess the degree of each expert's authority. Consensus was achieved following the two survey rounds and several iterations among the experts. For TB health-promotion activities directed at policymakers, the experts reached consensus on 2 domains ("Resource inputs" and "Policymaking and monitoring behaviors"), 4 subdomains ("Human resources" among others), and 13 indicators ("Human resources per 100,000 person" among others). For TB health-promotion activities directed at HCWs, the experts reached consensus on 5 domains ("Self-protective behaviors" among others), 6 sub-domains ("Preventing infection" among others), and 15 indicators ("Average hours of daily workplace disinfection by ultraviolet radiation" among others). This study identified a conceptual framework of core behavioral indicators to evaluate TB health-promotion activities directed at policymakers and HCWs involved in TB control. Validation in other parts of the world could lead to global consensus on behavioral indicators to evaluate TB health promotion targeted at policymakers and HCWs.

[Women's knowledge, perceptions, beliefs, and behaviors related to tuberculosis: results from a survey with participants of seminars held by the National Federation of Community Women's Organizations for Tuberculosis Control].

PubMed

Akishinonomiya, Kiko

2012-10-01

With an aim of advancing knowledge: that supports strategies for tuberculosis (TB) prevention, the current study was designed (1) to examine knowledge, perceptions, beliefs, and behaviors towards general health and diseases, including TB, and (2) to explore relationships among knowledge, perceptions, beliefs of TB, and TB prevention behaviors. Questionnaire surveys were conducted for 827 study participants who were attendees of seminars held by the National Federation of Community Women's Organizations for TB Control and the Japan Anti-Tuberculosis Association, between February 2010 and February 2011. More than 70% of the participants understood correctly such general facts on TB as the necessity of TB examinations for those who had contact with TB patients and individuals whose coughing persists for more than two weeks, and differences between TB infection and active TB disease. Only 30% to 40% of the participants answered correctly questions about epidemiological facts on TB, such as "TB infection tends to progress to active TB disease within one year," or "The proportion of individuals who develop active disease after TB infection is less than one fifth." The study participants perceived their susceptibility to TB to be significantly lower than that of the average peer, suggesting that so-called "optimistic bias," a cognitive bias, should exist on this matter. Those study participants who do not have personal history of TB nor contact with TB patients tend to perceive their susceptibility to be significantly lower than those who have. There were statistically significant gaps between intentions to prevent TB and actual behaviors taken to prevent it. The results from the current survey revealed several aspects of TB that are not fully understood yet. It is suggested that it should still remain important for healthcare providers in Japan to disseminate accurate and detailed knowledge on TB to the public in more easy-to-understand formats. Findings on optimistic bias and gaps between intentions and behaviors imply the needs for closer considerations to diverse psychological facets in the process of designing of disease prevention programs. Future investigations on psychological aspects of disease prevention behaviors are recommended in order to promote effective preventions of TB.

[Treatment of tuberculosis].

PubMed

Ben Amar, J; Dhahri, B; Aouina, H; Azzabi, S; Baccar, M A; El Gharbi, L; Bouacha, H

2015-01-01

The aim of this article is to give practicing physicians a practical approach to the treatment of latent and active tuberculosis. Most patients follow TB standard treatment recommended by WHO that depend on category of patient. It is a combination of four essential tuberculosis drugs of the first group: isoniazid, rifampicin, pyrazinamid and ethambutol; in some cases streptomycin can replace ethambutol. This initial phase of intensive treatment is followed by a consolidation phase. Drugs should be administered in the morning on an empty stomach one hour before meals. Treatment of latent tuberculosis (TB) infection is an important component of TB control programs. Preventive treatment can reduce the risk of developing active TB. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Translating childhood tuberculosis case management research into operational policies.

PubMed

Safdar, N; Hinderaker, S G; Baloch, N A; Enarson, D A; Khan, M A; Morkve, O

2011-08-01

The control of childhood tuberculosis (TB) has been of low priority in TB programmes in high-burden settings. The objective of this paper was to describe the development and testing of tools for the management of childhood TB. The Pakistan National TB Control Programme embarked on a number of activities, including the establishment of policy guidelines for the management of childhood TB and later a guidance document, 'Case Management Desk Guide and Structured Monitoring', to demonstrate the implementation of childhood TB interventions in a programme context. Initial results showed improved case finding and treatment outcome in implementation sites compared with control districts. However, further programme attention is required to improve quality.

Tuberculosis elimination in the post Millennium Development Goals era.

PubMed

Wejse, Christian

2015-03-01

The Millennium Development Goal for tuberculosis (TB) is to stop the increase in incidence and halve the mortality of TB between 1990 and 2015. This goal has now been reached on a global scale, although not in the most affected region of Africa. The new target is TB elimination, defined as one case of active TB per one million population per year, which is to be reached before 2050. This review will discuss the main tools in play, namely case-finding and new diagnostics, increased access and effectiveness of anti-TB therapy (directly observed therapy, short course (DOTS)), preventive therapy for latent infection, and vaccination. Each approach is discussed and a way forward in research and management is suggested. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

Tuberculosis outbreak investigation of a U.S. Navy amphibious ship crew and the Marine expeditionary unit aboard, 1998.

PubMed

Lamar, James E; Malakooti, Mark A

2003-07-01

A Marine deployed aboard a U.S. Navy amphibious ship had smear-positive, cavitary pulmonary tuberculosis (TB). Contact investigation ultimately found 21 active cases of TB among sailors and Marines who were aboard the affected ship. Approximately 3 months lapsed between onset of the source patient's illness and appropriate diagnosis and treatment. During the contact investigation, 3,338 persons received tuberculin skin tests and 712 were identified as new latent tuberculosis infection cases. Four persons diagnosed with latent tuberculosis infection developed active TB because of poor compliance with treatment. After personnel disembarked from the ship, persistent efforts to identify persons with active disease and latent infections were successful in controlling further spread of tuberculosis in military units and local communities. The Mycobacterium tuberculosis bacteria isolated from the source patient and 16 of the other active cases were susceptible to all drugs commonly used to treat TB.

The prevalence and determinants of active tuberculosis among diabetes patients in Cape Town, South Africa, a high HIV/TB burden setting.

PubMed

Berkowitz, Natacha; Okorie, Adaeze; Goliath, Rene; Levitt, Naomi; Wilkinson, Robert J; Oni, Tolu

2018-04-01

Studies addressing the association between diabetes mellitus (DM) and tuberculosis (TB) in sub-Saharan Africa are limited. We assessed the prevalence of active TB among DM patients at a primary care clinic, and identified risk factors for prevalent TB. A cross-sectional study was conducted in adult DM patients attending a clinic in Khayelitsha, Cape Town. Participants were screened for active TB (symptom screening and microbiological diagnosis) and HIV. Among 440 DM patients screened, the active TB prevalence was 3.0% (95% CI 1.72-5.03). Of the 13 prevalent TB cases, 53.9% (n = 7; 95% CI 27.20-78.50) had no TB symptoms, and 61.5% (n = 8; 95% CI 33.30-83.70) were HIV-1 co-infected. There were no significant differences in either fasting plasma glucose or HbA 1c levels between TB and non-TB participants. On multivariate analysis, HIV-1 infection (OR 11.3, 95% CI 3.26-39.42) and hemoptysis (OR 31.4, 95% CI 3.62-273.35) were strongly associated with prevalent active TB, with no differences in this association by age or gender. The prevalence of active TB among DM patients was 4-fold higher than the national prevalence; suggesting the need for active TB screening, particularly if hemoptysis is reported. Our results highlight the importance of HIV screening in this older population group. The high prevalence of sub-clinical TB among those diagnosed with TB highlights the need for further research to determine how best to screen for active TB in high-risk TB/HIV population groups and settings. Copyright © 2018. Published by Elsevier B.V.

Tuberculosis among Dislocated North Koreans Entering Republic of Korea since 1999

PubMed Central

Choi, Chang-Min; June, Jung-Hee; Kang, Cheol-In; Park, Jung-Tak; Oh, Soo-Yon; Lee, Jin-Beom; Lee, Chang-Hoon; Yim, Jae-Joon

2007-01-01

The collapse of North Korea's public health system has increased the development of tuberculosis (TB) in its populace. This study investigated the prevalence of active and latent TB infection (LTBI) in such people who have settled in the Republic of Korea since 1999. From 1999 to August 2006, 7,722 dislocated North Koreans entered the Republic of Korea and all were screened immediately for active TB. Demographic and clinical characteristics were reviewed from the official records of the Settlement Support Office for Dislocated North Koreans, based in the Ministry of Unification. Of 7,722 participants, 87 (1.13%) were diagnosed with active TB from 1999 to August 2006. Of these, 78 (90%) had pulmonary TB. Checking for the presence of a Bacille Calmette-Guérin (BCG) scar and tuberculin skin test has been performed in all dislocated North Koreans since November 2005. Of 1,112 participants, BCG vaccination scars were found in 67.4%. The tuberculin-positive rate using two tuberculin unit doses of the purified protein derivative RT23 (≥10 mm in diameter) was 81.5%. The prevalence of active TB and LTBI in dislocated North Koreans was high. Because this group bears a disproportionate burden of TB, we need to initiate a specific control programme and to plan for the impact of this disease in the Republic of Korea. PMID:18162707

Tuberculosis among dislocated North Koreans entering Republic of Korea since 1999.

PubMed

Choi, Chang Min; June, Jung Hee; Kang, Cheol In; Park, Jung Tak; Oh, Soo Yon; Lee, Jin Beom; Lee, Chang Hoon; Yim, Jae Joon; Kim, Hee Jin

2007-12-01

The collapse of North Korea's public health system has increased the development of tuberculosis (TB) in its populace. This study investigated the prevalence of active and latent TB infection (LTBI) in such people who have settled in the Republic of Korea since 1999. From 1999 to August 2006, 7,722 dislocated North Koreans entered the Republic of Korea and all were screened immediately for active TB. Demographic and clinical characteristics were reviewed from the official records of the Settlement Support Office for Dislocated North Koreans, based in the Ministry of Unification. Of 7,722 participants, 87 (1.13%) were diagnosed with active TB from 1999 to August 2006. Of these, 78 (90%) had pulmonary TB. Checking for the presence of a Bacille Calmette-Guerin (BCG) scar and tuberculin skin test has been performed in all dislocated North Koreans since November 2005. Of 1,112 participants, BCG vaccination scars were found in 67.4%. The tuberculin-positive rate using two tuberculin unit doses of the purified protein derivative RT23 (> or =10mm in diameter) was 81.5%. The prevalence of active TB and LTBI in dislocated North Koreans was high. Because this group bears a disproportionate burden of TB, we need to initiate a specific control programme and to plan for the impact of this disease in the Republic of Korea.

The present and the future of AIDS and tuberculosis in Illinois.

PubMed Central

Coté, T R; Nelson, M R; Anderson, S P; Martin, R J

1990-01-01

The relation between the acquired immune deficiency syndrome (AIDS) and tuberculosis (TB) was examined by matching the Illinois AIDS and TB registries. The match group was examined and compared with patients with only one disease by race, method of human immunodeficiency virus (HIV) transmission, site of tuberculous disease, radiographic findings, and results of Mantoux tests. The time of TB diagnosis was centrally distributed around the time of AIDS diagnosis; from this, it was determined that 4.1 percent of AIDS patients develop active TB. Projections for future AIDS cases were made by fitting a polynomial model to historical data. These projections were then used to predict the future impact of AIDS-related TB upon state TB rates. The rise in TB rates call for special efforts to minimize this impact. PMID:2368856

Epigenetics and Proteomics Join Transcriptomics in the Quest for Tuberculosis Biomarkers

PubMed Central

Esterhuyse, Maria M.; Weiner, January; Caron, Etienne; Loxton, Andre G.; Iannaccone, Marco; Wagman, Chandre; Saikali, Philippe; Stanley, Kim; Wolski, Witold E.; Mollenkopf, Hans-Joachim; Schick, Matthias; Aebersold, Ruedi; Linhart, Heinz; Walzl, Gerhard

2015-01-01

ABSTRACT An estimated one-third of the world’s population is currently latently infected with Mycobacterium tuberculosis. Latent M. tuberculosis infection (LTBI) progresses into active tuberculosis (TB) disease in ~5 to 10% of infected individuals. Diagnostic and prognostic biomarkers to monitor disease progression are urgently needed to ensure better care for TB patients and to decrease the spread of TB. Biomarker development is primarily based on transcriptomics. Our understanding of biology combined with evolving technical advances in high-throughput techniques led us to investigate the possibility of additional platforms (epigenetics and proteomics) in the quest to (i) understand the biology of the TB host response and (ii) search for multiplatform biosignatures in TB. We engaged in a pilot study to interrogate the DNA methylome, transcriptome, and proteome in selected monocytes and granulocytes from TB patients and healthy LTBI participants. Our study provides first insights into the levels and sources of diversity in the epigenome and proteome among TB patients and LTBI controls, despite limitations due to small sample size. Functionally the differences between the infection phenotypes (LTBI versus active TB) observed in the different platforms were congruent, thereby suggesting regulation of function not only at the transcriptional level but also by DNA methylation and microRNA. Thus, our data argue for the development of a large-scale study of the DNA methylome, with particular attention to study design in accounting for variation based on gender, age, and cell type. PMID:26374119

Differential Levels of Alpha-2-Macroglobulin, Haptoglobin and Sero-Transferrin as Adjunct Markers for TB Diagnosis and Disease Progression in the Malnourished Tribal Population of Melghat, India

PubMed Central

Bapat, Prachi R.; Satav, Ashish R.; Husain, Aliabbas A.; Shekhawat, Seema D.; Kawle, Anuja P.; Chu, Justin J.; Purohit, Hemant J.; Daginawala, Hatim F.; Taori, Girdhar M.; Kashyap, Rajpal S.

2015-01-01

Lack of diagnostic capacity has been a crucial barrier preventing an effective response to the challenges of malnutrition and tuberculosis (TB). Point-of-care diagnostic tests for TB in immuno-incompetent, malnourished population are thus needed to ensure rapid and accurate detection. The aim of the study was to identify potential biomarkers specific for TB infection and progression to overt disease in the malnourished population of Melghat. A prospective cohort study was conducted in the year 2009 through 2011 in six villages of the Melghat region. 275 participants consisting of malnourished cases with a) active TB (n = 32), b) latent TB infection (n = 90), c) with no clinical or bacteriological signs of active or latent TB (n = 130) and healthy control subjects (n = 23) were recruited for the study. The proteome changes of the host serum in response to Mycobacterium tuberculosis (M.tb) infection were investigated using one dimensional electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Three most differentially expressed proteins; alpha-2-macroglobulin (A-2-M), sero-transferrin and haptoglobin were identified by MALDI-TOF MS analysis, which were up-regulated in the malnourished patients with active TB and down-regulated in the malnourished patients compared with the healthy controls. Additionally, follow-up studies indicated that the expression of these proteins increased to nearly two folds in patients who developed active disease from latent state. Our preliminary results suggest that A-2-M, sero-transferrin and haptoglobin may be clinically relevant host biomarkers for TB diagnosis and disease progression in the malnourished population. This study provides preliminary framework for an in-depth analysis of the biomarkers in larger well-characterized cohorts. Evaluation of these biomarkers in follow-up cases may further aid in improving TB diagnosis. PMID:26241963

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: risk assessment.

PubMed

Park, Dong Il; Hisamatsu, Tadakazu; Chen, Minhu; Ng, Siew Chien; Ooi, Choon Jin; Wei, Shu Chen; Banerjee, Rupa; Hilmi, Ida Normiha; Jeen, Yoon Tae; Han, Dong Soo; Kim, Hyo Jong; Ran, Zhihua; Wu, Kaichun; Qian, Jiaming; Hu, Pin-Jin; Matsuoka, Katsuyoshi; Andoh, Akira; Suzuki, Yasuo; Sugano, Kentaro; Watanabe, Mamoru; Hibi, Toshifumi; Puri, Amarender S; Yang, Suk-Kyun

2018-01-01

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised 2 parts: risk of TB infection Recommendaduring anti-TNF therapy, and screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: risk assessment

PubMed Central

Park, Dong Il; Hisamatsu, Tadakazu; Chen, Minhu; Ng, Siew Chien; Ooi, Choon Jin; Wei, Shu Chen; Banerjee, Rupa; Hilmi, Ida Normiha; Jeen, Yoon Tae; Han, Dong Soo; Kim, Hyo Jong; Ran, Zhihua; Wu, Kaichun; Qian, Jiaming; Hu, Pin-Jin; Matsuoka, Katsuyoshi; Andoh, Akira; Suzuki, Yasuo; Sugano, Kentaro; Watanabe, Mamoru; Hibi, Toshifumi; Puri, Amarender S.

2018-01-01

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised 2 parts: risk of TB infection Recommendaduring anti-TNF therapy, and screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment. PMID:29422793

Dihydrolipoamide dehydrogenase-Lpd (Rv0462)-specific T cell recall responses are higher in healthy household contacts of TB: a novel immunodominant antigen from M. tuberculosis.

PubMed

Devasundaram, Santhi; Raja, Alamelu

2017-07-01

The partial effectiveness against pulmonary tuberculosis (PTB), displayed by the existing tuberculosis (TB) vaccine, bacillus Calmette-Guérin (BCG), highlights the need for novel vaccines to replace or improve BCG. In TB immunology, antigen-specific cellular immune response is frequently considered indispensable. Latency-associated antigens are intriguing as targets for TB vaccine development. The mycobacterial protein, dihydrolipoamide dehydrogenase (Lpd; Rv0462), the third enzyme of the pyruvate dehydrogenase (PDH) complex, facilitates Mycobacterium tuberculosis to resist host reactive nitrogen intermediates. Multicolor flow cytometry analysis of whole-blood cultures showed higher Lpd-specific Th1 recall response (IFN-γ, TNF-α, and IL-2; P = 0.0006) and memory CD4 + and CD8 + T cells (CCR7 + CD45RA - and CCR7 - CD45RA - ) in healthy household contacts (HHC) of TB ( P < 0.0001), which is comparable with or higher than the standard antigens, ESAT-6 and CFP-10. The frequency of Lpd-specific multifunctional T cells was higher in HHC compared with PTB patients. However, there is no significant statistical correlation. Regulatory T cell (T reg ) analysis of HHCs and active TB patients demonstrated very low Lpd-specific CD4 + T regs relative to ESAT-6 and CFP-10. Our study demonstrates that the Lpd antigen induces a strong cellular immune response in healthy mycobacteria-infected individuals. In consideration of this population having demonstrated immunologic protection against active TB disease development, our data are encouraging about the possible use of Lpd as a target for further TB subunit vaccine development. © Society for Leukocyte Biology.

New hydrazides derivatives of isoniazid against Mycobacterium tuberculosis: Higher potency and lower hepatocytotoxicity.

PubMed

Castelo-Branco, Frederico Silva; de Lima, Evanoel Crizanto; Domingos, Jorge Luiz de Oliveira; Pinto, Angelo C; Lourenço, Maria Cristina S; Gomes, Karen Machado; Costa-Lima, Mariana Marques; Araujo-Lima, Carlos Fernando; Aiub, Claudia Alessandra Fortes; Felzenszwalb, Israel; Costa, Thadeu Estevam M M; Penido, Carmen; Henriques, Maria G; Boechat, Nubia

2018-02-25

Tuberculosis (TB) is one of the leading causes of death worldwide. The emergence of multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) and TB-HIV co-infection are major public health challenges. The anti-TB drugs of first choice were developed more than 4 decades ago and present several adverse effects, making the treatment of TB even more complicated and the development of new chemotherapeutics for this disease imperative. In this work, we synthesized two series of new acylhydrazides and evaluated their activity against different strains of Mtb. Derivatives of isoniazid (INH) showed important anti-Mtb activity, some being more potent than all anti-TB drugs of first choice. Moreover, three compounds proved to be more potent than INH against resistant Mtb. The Ames test showed favorable results for two of these substances compared to INH, one of which presented expressly lower toxicity to HepG2 cells than that of INH. This result shows that this compound has the potential to overcome one of the main adverse effects of this drug. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Plants in our combating strategies against Mycobacterium tuberculosis: progress made and obstacles met.

PubMed

Gupta, Vivek Kumar; Kumar, M Madhan; Bisht, Deepa; Kaushik, Anupam

2017-12-01

Traditionally used plants for treating chest-related problems/tuberculosis (TB) have not been evaluated in detail and hence a thorough study is needed in this regard. This knowledge may find application in developing new anti-TB drugs. This article elaborates on studying the activity of medicinal plants against different forms of Mycobacterium tuberculosis (Mtb) using different model strains, in vitro and ex vivo assays for studying the tuberculocidal activity and discusses the results from different studies on the activity against different forms of Mtb and human immunodeficiency virus-tuberculosis (HIV-TB) co-infection. Scientific databases such as PubMed, Elsevier, Scopus, Google scholar, were used to retrieve the information from 86 research articles (published from 1994 to 2016) related to the topic of this review. Twenty-three plant species have been reported to possess active molecules against multi-drug resistant (MDR) isolates of Mtb. Seven plants were found to be active against intracellular Mtb and six against dormant bacilli. Seven plants were synergistically effective when combined with anti-TB drugs. Six studies suggest that the beneficial effects of plant extracts are due to their wide array of immuno-modulatory effects manifested by the higher expression of cytokines. Some studies have also shown the dual activity (anti-HIV and anti-TB) of plants. We emphasize on identifying plants based on traditional uses and testing their extracts/phytomolecules against MDR strains, intracellular Mtb as well as against dormant Mtb. This will help in future to shorten the current therapeutic regimens for TB and also for treating HIV-TB co-infection.

[Screening program for tuberculosis among international exchange students in the Department of Isère].

PubMed

Albahary, M-V; Blanc-Jouvan, F; Recule, C; Dubey, C; Pavese, P

2018-01-01

France is a low-incidence country for tuberculosis (TB). Consequently screening is focused on high-risk populations, in particular migrants. The aim of this study was to evaluate the epidemiology of TB among international exchange students in the Department of Isère and the screening programs used. We carried out an organizational audit based on interviews with physicians involved in the management of TB in Isère. We conducted a retrospective descriptive study based on a case series of foreign students treated for TB from 2003 to 2013 inclusively. Forty-six international exchange students were treated for active TB during this time, representing an average incidence of 284/100,000. Two thirds of our studied population were Africans, 72% were asymptomatic at the time of screening. A quarter of our cohort developed TB after the initial screening. Thirty-one cases were confirmed bacteriologically, mainly through bronchoscopy. Outcome (radiological and clinical) on quadruple therapy was satisfactory in all patients. Two patients relapsed, one of them with multi-drug resistant TB. Our work confirms that international exchange students are a population at high risk of TB and that screening of this population is essential. The significant number of active TB cases diagnosed after the initial screening stresses the importance of diagnosis and follow up of patients with latent TB infection. Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Processing of metacaspase 2 from Trypanosoma brucei (TbMCA2) broadens its substrate specificity.

PubMed

Gilio, Joyce M; Marcondes, Marcelo F; Ferrari, Débora; Juliano, Maria A; Juliano, Luiz; Oliveira, Vitor; Machado, Maurício F M

2017-04-01

Metacaspases are members of the cysteine peptidase family and may be implicated in programmed cell death in plants and lower eukaryotes. These proteases exhibit calcium-dependent activity and specificity for arginine residues at P 1 . In contrast to caspases, they do not require processing or dimerization for activity. Indeed, unprocessed metacaspase-2 of Trypanosoma brucei (TbMCA2) is active; however, it has been shown that cleavages at Lys 55 and Lys 268 increase TbMCA2 hydrolytic activity on synthetic substrates. The processed TbMCA2 comprises 3 polypeptide chains that remain attached by non-covalent bonds. Replacement of Lys 55 and Lys 268 with Gly via site-directed mutagenesis results in non-processed but enzymatically active mutant, TbMCA2 K55/268G. To investigate the importance of this processing for the activity and specificity of TbMCA2, we performed activity assays comparing the non-processed mutant (TbMCA2 K55/268G) with the processed TbMCA2 form. Significant differences between TbMCA2 WT (processed form) and TbMCA2 K55/268G (non-processed form) were observed. Specifically, we verified that although non-processed TbMCA2 is active when assayed with small synthetic substrates, the TbMCA2 form does not exhibit hydrolytic activity on large substrates such as azocasein, while processed TbMCA2 is able to readily digest this protein. Such differences can be relevant for understanding the physiological regulation and function of TbMCA2. Copyright © 2017 Elsevier B.V. All rights reserved.

C-Reactive Protein (CRP), Interferon Gamma-Inducible Protein 10 (IP-10), and Lipopolysaccharide (LPS) Are Associated with Risk of Tuberculosis after Initiation of Antiretroviral Therapy in Resource-Limited Settings

PubMed Central

Tenforde, Mark W.; Gupte, Nikhil; Dowdy, David W.; Asmuth, David M.; Balagopal, Ashwin; Pollard, Richard B.; Sugandhavesa, Patcharaphan; Lama, Javier R.; Pillay, Sandy; Cardoso, Sandra W.; Pawar, Jyoti; Santos, Breno; Riviere, Cynthia; Mwelase, Noluthando; Kanyama, Cecilia; Kumwenda, Johnstone; Hakim, James G.; Kumarasamy, Nagalingeswaran; Bollinger, Robert; Semba, Richard D.; Campbell, Thomas B.; Gupta, Amita

2015-01-01

Objective The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain. Design Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naïve adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm). Methods We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-γ), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis. Results Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55–6.81) and IP-10 (aOR 1.89, 95% CI: 1.05–3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13–5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB. Conclusion Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators. PMID:25719208

Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques

PubMed Central

Lin, Philana Ling; Dartois, Veronique; Johnston, Paul J.; Janssen, Christopher; Via, Laura; Goodwin, Michael B.; Klein, Edwin; Barry, Clifton E.; Flynn, JoAnne L.

2012-01-01

Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential to shorten therapy for active tuberculosis (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. tuberculosis infection, equal proportions of cynomolgus macaques develop active disease or latent infection and that latently infected animals reactivated upon neutralization of TNF. Using this model we now show that chemoprophylaxis of latently infected cynomolgus macaques with 6 mo of isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment of latent animals with a combination of INH and rifampicin (RIF) was highly effective at preventing reactivation disease in this model. Metronidazole (MTZ), which has activity only against anaerobic, nonreplicating bacteria, was as effective as either of these treatments in preventing reactivation of latent infection. Because hypoxic lesions also occur during active TB, we further showed that addition of MTZ to INH/RIF effectively treated animals with active TB within 2 mo. Healing lesions were associated with distinct changes in cellular pathology, with a shift toward increasingly fibrotic and calcified lesions. Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB. PMID:22826237

A comparative examination of tuberculosis immigration medical screening programs from selected countries with high immigration and low tuberculosis incidence rates

PubMed Central

2011-01-01

Background Tuberculosis (TB) in migrants is an ongoing challenge in several low TB incidence countries since a large proportion of TB in these countries occurs in migrants from high incidence countries. To meet these challenges, several countries utilize TB screening programs. The programs attempt to identify and treat those with active and/or infectious stages of the disease. In addition, screening is used to identify and manage those with latent or inactive disease after arrival. Between nations, considerable variation exists in the methods used in migration-associated TB screening. The present study aimed to compare the TB immigration medical examination requirements in selected countries of high immigration and low TB incidence rates. Methods Descriptive study of immigration TB screening programs Results 16 out of 18 eligible countries responded to the written standardized survey and phone interview. Comparisons in specific areas of TB immigration screening programs included authorities responsible for TB screening, the primary objectives of the TB screening program, the yield of detection of active TB disease, screening details and aspects of follow up for inactive pulmonary TB. No two countries had the same approach to TB screening among migrants. Important differences, common practices, common problems, evidence or lack of evidence for program specifics were noted. Conclusions In spite of common goals, there is great diversity in the processes and practices designed to mitigate the impact of migration-associated TB among nations that screen migrants for the disease. The long-term goal in decreasing migration-related introduction of TB from high to low incidence countries remains diminishing the prevalence of the disease in those high incidence locations. In the meantime, existing or planned migration screening programs for TB can be made more efficient and evidenced based. Cooperation among countries doing research in the areas outlined in this study should facilitate the development of improved screening programs. PMID:21205318

2-Thiophenecarboxylic acid hydrazide Derivatives: Synthesis and Anti-Tuberculosis Studies

NASA Astrophysics Data System (ADS)

Fahmi, M. R. G.; Khumaidah, L.; Ilmiah, T. K.; Fadlan, A.; Santoso, M.

2018-04-01

One of the most frequent and widespread infectious diseases especially in developing countries is tuberculosis (TB). The number of TB drug resistant tend to increase, and there has been no new TB drug introduce since the 1960s. Six 2-Thiophenecarboxylic acid hydrazide derivatives were synthesized in 90-97% yields, and 2-thiophenecarbonylhydrazone-5, 7-dibromoisatin showed the highest activity in inhibiting M. tuberculosis H37Rv.

Reactivation of Latent Tuberculosis in Cynomolgus Macaques Infected with SIV Is Associated with Early Peripheral T Cell Depletion and Not Virus Load

PubMed Central

Klein, Edwin; Janssen, Chris; Phuah, Jiayao; Sturgeon, Timothy J.; Montelaro, Ronald C.; Lin, Philana Ling; Flynn, JoAnne L.

2010-01-01

HIV-infected individuals with latent Mycobacterium tuberculosis (Mtb) infection are at significantly greater risk of reactivation tuberculosis (TB) than HIV-negative individuals with latent TB, even while CD4 T cell numbers are well preserved. Factors underlying high rates of reactivation are poorly understood and investigative tools are limited. We used cynomolgus macaques with latent TB co-infected with SIVmac251 to develop the first animal model of reactivated TB in HIV-infected humans to better explore these factors. All latent animals developed reactivated TB following SIV infection, with a variable time to reactivation (up to 11 months post-SIV). Reactivation was independent of virus load but correlated with depletion of peripheral T cells during acute SIV infection. Animals experiencing reactivation early after SIV infection (<17 weeks) had fewer CD4 T cells in the periphery and airways than animals reactivating in later phases of SIV infection. Co-infected animals had fewer T cells in involved lungs than SIV-negative animals with active TB despite similar T cell numbers in draining lymph nodes. Granulomas from these animals demonstrated histopathologic characteristics consistent with a chronically active disease process. These results suggest initial T cell depletion may strongly influence outcomes of HIV-Mtb co-infection. PMID:20224771

Modified directly observed treatment for tuberculosis versus self-administered therapy: an observational study in rural Greece.

PubMed

Charokopos, N; Tsiros, G; Foka, A; Voila, P; Chrysanthopoulos, K; Spiliopoulou, I; Jelastopulu, E

2013-01-01

Directly Observed Treatment (DOT) is the key element of DOTS (directly observed treatment, short course), part of the internationally recommended control strategy for tuberculosis (TB). The evaluation of DOT has not been widely evaluated in rural areas in developed settings. The aim of this pilot study was to evaluate a modified DOT program (MDOT) by a general practitioner (GP) in a rural area of southwest Greece, where there is substantial underreporting of TB cases. Thirteen new TB cases with 30 close contacts were compared with 41 past-treated TB subjects (controls) with 111 close contacts in this observational, case-control study. Home visits by a GP were conducted and comparison of various data (laboratory findings, treatment outcomes, questionnaire-based parameters, on-site recorded conditions) was performed in both newly detected pulmonary TB cases and previously treated TB cases managed without DOT intervention. MDOT by GP implementation revealed that 11 cases (84.6%) were successfully treated, one (7.7%) case died, and one (7.7%) was lost to follow up. None of the close contacts of new TB cases was infected with active TB, while 6.3% of previously-treated TB subjects were infected with active TB and had to receive a complete anti-TB regimen. Chemoprophylaxis was administered to 13.3% of close contacts of new cases; whereas 12.6% of close contacts of previously-treated patients received chemoprophylaxis. This pilot study revealed that a GP is able to implement a program based on DOT resulting in high treatment adherence and prevention of TB compared with the conventional self-administration of treatment.

Is systematic screening and treatment for latent tuberculosis infection in HIV patients useful in a low endemic setting?

PubMed

Maniewski, Ula; Payen, Marie-Christine; Delforge, Marc; De Wit, Stephane

2017-08-01

A decreasing incidence of tuberculosis (TB) among HIV patients has been documented in high-income settings and screening for tuberculosis is not systematically performed in many clinics (such as ours). Our objectives are to evaluate whether a same decline of incidence was seen in our Belgian tertiary center and to evaluate whether systematic screening and prophylaxis of tuberculosis should remain part of routine practice. Between 2005 and 2012, the annual incidence of tuberculosis among adult HIV patients was measured. The impact of demographic characteristics and CD 4 nadir on the incidence of active TB was evaluated. Among the 1167 patients who entered the cohort, 42 developed active TB with a significant decrease of annual incidence from 28/1000 patient-years in 2005 to 3/1000 patient-years in 2012. Among the 42 cases, 83% were of sub-Saharan origin. Median CD4 cell count upon HIV diagnosis was significantly lower in TB cases and 60% had a nadir CD4 below 200/μl. Thirty-six percent of incident TB occurred within 14 days after HIV diagnosis. A significant decline of TB incidence in HIV patients was observed. Incident TB occurred mainly in African patients, with low CD4 upon HIV diagnosis. A significant proportion of TB cases were discovered early in follow-up which probably reflects TB already present upon HIV diagnosis. In a low endemic setting, exclusion of active TB upon HIV diagnosis remains a priority and screening for LTBI should focus on HIV patients from high risk groups such as migrants from endemic regions, especially in patients with low CD4 nadir.

Tuberculin survey among school-aged children in Ahvaz, Iran, 2006.

PubMed

Alavi, Seyed Mohammad; Sefidgaran, Gholam Hossein

2008-07-01

The tuberculin test is widely used for the diagnosis of tuberculosis (TB) in children, as it is the only one to provide evidence of infection with Mycobacterium tuberculosis. Our objective was to estimate the prevalence of TB infection, the annual risk of infection (ARI), and the incidence of active TB in school children. A cross-sectional study was carried out in Ahvaz, a city of southern Iran, in 2006. A questionnaire was used to collect information, including demographic characteristics, bacillus Calmette-Guérin (BCG) vaccination history, and household contact with active TB. Tuberculin testing was performed. Reactivity that measured < 5 mm was considered negative, between 5 and 9 mm was considered doubtful, and > or = 10mm was considered positive. Chest radiographs were obtained as part of the evaluation for children with a positive result. A total of 3906 children with a mean+/-standard deviation (SD) age of 10.59+/-2.63 years (51% female, 49% male) were entered into our study. Of these, 3338 children (85.5%) did not develop a reaction (0mm), 243 (6.2%) had reactivity of 1-4mm, 238 (6.1%) had reactivity of 5-9 mm, and 87 (2.2%) had reactivity of > or = 10 mm. More than 90% of the children had received the BCG vaccine in the first week of life. The ARI rate was 0.5% and the estimated case of smear-positive TB was approximately 25 per 100000 population. Only three children were diagnosed with active TB, a prevalence of 75 per 100000 population. Tuberculin testing using 5TU-PPD (5 tuberculin units of purified protein derivative) is a valuable diagnostic test for latent TB and active TB in childhood. BCG vaccination has no remarkable effect on the interpretation of tuberculin reactivity. The incidence rate of active pulmonary TB in children in the region of study is of concern.

Target prioritization and strategy selection for active case-finding of pulmonary tuberculosis: a tool to support country-level project planning.

PubMed

Nishikiori, Nobuyuki; Van Weezenbeek, Catharina

2013-02-02

Despite the progress made in the past decade, tuberculosis (TB) control still faces significant challenges. In many countries with declining TB incidence, the disease tends to concentrate in vulnerable populations that often have limited access to health care. In light of the limitations of the current case-finding approach and the global urgency to improve case detection, active case-finding (ACF) has been suggested as an important complementary strategy to accelerate tuberculosis control especially among high-risk populations. The present exercise aims to develop a model that can be used for county-level project planning. A simple deterministic model was developed to calculate the number of estimated TB cases diagnosed and the associated costs of diagnosis. The model was designed to compare cost-effectiveness parameters, such as the cost per case detected, for different diagnostic algorithms when they are applied to different risk populations. The model was transformed into a web-based tool that can support national TB programmes and civil society partners in designing ACF activities. According to the model output, tuberculosis active case-finding can be a costly endeavor, depending on the target population and the diagnostic strategy. The analysis suggests the following: (1) Active case-finding activities are cost-effective only if the tuberculosis prevalence among the target population is high. (2) Extensive diagnostic methods (e.g. X-ray screening for the entire group, use of sputum culture or molecular diagnostics) can be applied only to very high-risk groups such as TB contacts, prisoners or people living with human immunodeficiency virus (HIV) infection. (3) Basic diagnostic approaches such as TB symptom screening are always applicable although the diagnostic yield is very limited. The cost-effectiveness parameter was sensitive to local diagnostic costs and the tuberculosis prevalence of target populations. The prioritization of appropriate target populations and careful selection of cost-effective diagnostic strategies are critical prerequisites for rational active case-finding activities. A decision to conduct such activities should be based on the setting-specific cost-effectiveness analysis and programmatic assessment. A web-based tool was developed and is available to support national tuberculosis programmes and partners in the formulation of cost-effective active case-finding activities at the national and subnational levels.

Tuberculosis Vaccines and Prevention of Infection

PubMed Central

Day, Tracey A.; Scriba, Thomas J.; Hatherill, Mark; Hanekom, Willem A.; Evans, Thomas G.; Churchyard, Gavin J.; Kublin, James G.; Bekker, Linda-Gail; Self, Steven G.

2014-01-01

SUMMARY Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than infection, has been the primary target for vaccine development. Several areas of research highlight the importance of including preinfection vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of infection, with evidence that host responses may be more effective during acute infection than during chronic infection. Third, natural history studies indicate that resistance to TB infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from infection. Fifth, prevention-of-infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB vaccine development efforts to include prevention of infection as a primary goal along with vaccines or other interventions that reduce the rate of transmission and reactivation. PMID:25428938

The Risk of Depressive Disorder Among Contacts of Tuberculosis Patients in a TB-endemic Area

PubMed Central

Pan, Sheng-Wei; Yen, Yung-Feng; Feng, Jia-Yih; Su, Vincent Yi-Fong; Kou, Yu Ru; Su, Wei-Juin

2015-01-01

Abstract Tuberculosis (TB) disease may be transmitted to close contacts of index cases, causing physical illness. No studies have investigated the risk of developing depressive disorder among TB contacts in a TB-endemic area. Adult participants with a new diagnosis of TB contact (ICD-9-CM codes V01.1 plus chest radiographic order) since January 1, 2008, were identified from the National Health Insurance Research Database in Taiwan. A control cohort matched for age (±5 y), sex, enrolled years, and income level was selected. These 2 cohorts were followed until December 31, 2012, and observed for the development of depressive disorder. The Kaplan-Meier method and the log-rank test were used to examine the difference in cumulative incidences of depressive disorder between groups. Cox proportional-hazard models were used to calculate adjusted hazard ratios (aHRs) for depressive disorder. The TB contact cohort consisted of 9046 patients and matched controls of 36,184 ones. The mean age of TB contacts was 44.7 years, and 56.0% of them were women. During a mean follow-up period of 2.5 years, 127 (1.40%) TB contacts and 521 (1.44%) matched controls developed depressive disorder. TB exposure was found to be an independent risk factor of depressive disorder in women (aHR 1.34, 95% confidence interval [CI] 1.07–1.68), but not in men (aHR 0.71, 95% CI 0.48–1.06) after adjusting for age, comorbidities, and income levels. The risk of depression was significantly higher for female TB contacts than for matched controls in the first and second years (aHR 1.49, 95% CI 1.03–2.14; and aHR 1.53, 95% CI 1.05–2.23, respectively), but not thereafter. Of note, 67 (0.74%) TB contacts and 88 (0.24%) matched controls developed active TB, but none of them had subsequent depressive disorder during follow-up periods. Female TB contacts had an increased risk of depression within the first 2 years after exposure. Clinicians should consider conducting depression evaluations in addition to routine TB contact investigations in this subgroup population. PMID:26512600

The Risk of Depressive Disorder Among Contacts of Tuberculosis Patients in a TB-endemic Area: A Population-based Cohort Study.

PubMed

Pan, Sheng-Wei; Yen, Yung-Feng; Feng, Jia-Yih; Su, Vincent Yi-Fong; Kou, Yu Ru; Su, Wei-Juin

2015-10-01

Tuberculosis (TB) disease may be transmitted to close contacts of index cases, causing physical illness. No studies have investigated the risk of developing depressive disorder among TB contacts in a TB-endemic area.Adult participants with a new diagnosis of TB contact (ICD-9-CM codes V01.1 plus chest radiographic order) since January 1, 2008, were identified from the National Health Insurance Research Database in Taiwan. A control cohort matched for age (±5 y), sex, enrolled years, and income level was selected. These 2 cohorts were followed until December 31, 2012, and observed for the development of depressive disorder. The Kaplan-Meier method and the log-rank test were used to examine the difference in cumulative incidences of depressive disorder between groups. Cox proportional-hazard models were used to calculate adjusted hazard ratios (aHRs) for depressive disorder.The TB contact cohort consisted of 9046 patients and matched controls of 36,184 ones. The mean age of TB contacts was 44.7 years, and 56.0% of them were women. During a mean follow-up period of 2.5 years, 127 (1.40%) TB contacts and 521 (1.44%) matched controls developed depressive disorder. TB exposure was found to be an independent risk factor of depressive disorder in women (aHR 1.34, 95% confidence interval [CI] 1.07-1.68), but not in men (aHR 0.71, 95% CI 0.48-1.06) after adjusting for age, comorbidities, and income levels. The risk of depression was significantly higher for female TB contacts than for matched controls in the first and second years (aHR 1.49, 95% CI 1.03-2.14; and aHR 1.53, 95% CI 1.05-2.23, respectively), but not thereafter. Of note, 67 (0.74%) TB contacts and 88 (0.24%) matched controls developed active TB, but none of them had subsequent depressive disorder during follow-up periods.Female TB contacts had an increased risk of depression within the first 2 years after exposure. Clinicians should consider conducting depression evaluations in addition to routine TB contact investigations in this subgroup population.

Considerations for biomarker-targeted intervention strategies for tuberculosis disease prevention.

PubMed

Fiore-Gartland, Andrew; Carpp, Lindsay N; Naidoo, Kogieleum; Thompson, Ethan; Zak, Daniel E; Self, Steve; Churchyard, Gavin; Walzl, Gerhard; Penn-Nicholson, Adam; Scriba, Thomas J; Hatherill, Mark

2018-03-01

Current diagnostic tests for Mycobacterium tuberculosis (MTB) infection have low prognostic specificity for identifying individuals who will develop tuberculosis (TB) disease, making mass preventive therapy strategies targeting all MTB-infected individuals impractical in high-burden TB countries. Here we discuss general considerations for a risk-targeted test-and-treat strategy based on a highly specific transcriptomic biomarker that can identify individuals who are most likely to progress to active TB disease as well as individuals with TB disease who have not yet presented for medical care. Such risk-targeted strategies may offer a rapid, ethical and cost-effective path towards decreasing the burden of TB disease and interrupting transmission and would also be critical to achieving TB elimination in countries nearing elimination. We also discuss design considerations for a Correlate of Risk Targeted Intervention Study (CORTIS), which could provide proof-of-concept for the strategy. One such study in South Africa is currently enrolling 1500 high-risk and 1700 low-risk individuals, as defined by biomarker status, and is randomizing high-risk participants to TB preventive therapy or standard of care treatment. All participants are monitored for progression to active TB with primary objectives to assess efficacy of the treatment and performance of the biomarker. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Optimal Control for TB disease with vaccination assuming endogeneous reactivation and exogeneous reinfection

NASA Astrophysics Data System (ADS)

Anggriani, N.; Wicaksono, B. C.; Supriatna, A. K.

2016-06-01

Tuberculosis (TB) is one of the deadliest infectious disease in the world which caused by Mycobacterium tuberculosis. The disease is spread through the air via the droplets from the infectious persons when they are coughing. The World Health Organization (WHO) has paid a special attention to the TB by providing some solution, for example by providing BCG vaccine that prevent an infected person from becoming an active infectious TB. In this paper we develop a mathematical model of the spread of the TB which assumes endogeneous reactivation and exogeneous reinfection factors. We also assume that some of the susceptible population are vaccinated. Furthermore we investigate the optimal vaccination level for the disease.

Evaluation of risk factors for false-negative results with an antigen-specific peripheral blood-based quantitative T cell assay (T-SPOT®. TB) in the diagnosis of active tuberculosis: A large-scale retrospective study in China.

PubMed

Yang, Chi; Zhang, Shaojun; Yao, Lan; Fan, Lin

2018-05-01

Objective To investigate the diagnostic efficacy of an interferon-γ release assay, T-SPOT ® . TB, for diagnosing active tuberculosis (TB) and to identify risk factors for false-negative results. Methods This retrospective study enrolled consecutive patients with active TB and with non-TB respiratory diseases to evaluate the risk factors for false-negative results when using the T-SPOT ® . TB assay for the diagnosis of active TB. Patients with active TB were categorized as having confirmed pulmonary TB, clinically diagnosed pulmonary TB or extrapulmonary TB (EPTB). Results This study analysed 4964 consecutive patients; 2425 with active TB and 2539 with non-TB respiratory diseases. Multivariate logistic regression analyses identified the following five factors that were all associated with an increased false-negative rate with the T-SPOT ® . TB assay: increased age (odds ratio [OR] 1.018; 95% confidence interval [CI] 1.013, 1.024); decreased CD8+ count (OR 0.307; 95% CI 0.117, 0.803); negative sputum acid-fast bacilli (AFB) smear staining (OR 1.821; 95% CI 1.338, 2.477); negative mycobacterial cultures (OR 1.379; 95% CI 1.043, 1.824); and absence of EPTB (OR 1.291; 95% CI 1.026, 1.623). Conclusions Increased age, decreased CD8+ count, negative sputum AFB smear results, negative sputum mycobacterial cultures and absence of EPTB might lead to an increased false-negative rate when using the T-SPOT ® . TB assay.

What's new in tuberculosis vaccines?

PubMed Central

Ginsberg, Ann M.

2002-01-01

Over the past 10 years, tuberculosis (TB) vaccine development has resurged as an active area of investigation. The renewed interest has been stimulated by the recognition that, although BCG is delivered to approximately 90% of all neonates globally through the Expanded Programme on Immunization, Mycobacterium tuberculosis continues to cause over 8 million new cases of TB and over 2 million deaths annually. Over one hundred TB vaccine candidates have been developed, using different approaches to inducing protective immunity. Candidate vaccines are typically screened in small animal models of primary TB disease for their ability to protect against a virulent strain of M. tuberculosis. The most promising are now beginning to enter human safety trials, marking real progress in this field for the first time in 80 years. PMID:12132007

The cursed duet today: Tuberculosis and HIV-coinfection.

PubMed

Tiberi, Simon; Carvalho, Anna Cristina C; Sulis, Giorgia; Vaghela, Devan; Rendon, Adrian; Mello, Fernanda C de Q; Rahman, Ananna; Matin, Nashaba; Zumla, Ali; Pontali, Emanuele

2017-03-01

The tuberculosis (TB) and HIV syndemic continues to rage and are a major public health concern worldwide. This deadly association raises complexity and represent a significant barrier towards TB elimination. TB continues to be the leading cause of death amongst HIV-infected people. This paper reports the challenges that lay ahead and outlines some of the current and future strategies that may be able to address this co-epidemic efficiently. Improved diagnostics, cheaper and more effective drugs, shorter treatment regimens for both drug-sensitive and drug-resistant TB are discussed. Also, special topics on drug interactions, TB-IRIS and TB relapse are also described. Notwithstanding the defeats and meagre investments, diagnosis and management of the two diseases have seen significant and unexpected improvements of late. On the HIV side, expansion of ART coverage, development of new updated guidelines aimed at the universal treatment of those infected, and the increasing availability of newer, more efficacious and less toxic drugs are an essential element to controlling the two epidemics. On the TB side, diagnosis of MDR-TB is becoming easier and faster thanks to the new PCR-based technologies, new anti-TB drugs active against both sensitive and resistant strains (i.e. bedaquiline and delamanid) have been developed and a few more are in the pipeline, new regimens (cheaper, shorter and/or more effective) have been introduced (such as the "Bangladesh regimen") or are being tested for MDR-TB and drug-sensitive-TB. However, still more resources will be required to implement an integrated approach, install new diagnostic tests, and develop simpler and shorter treatment regimens. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Asian Organization for Crohn's and Colitis and Asian Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: Risk assessment.

PubMed

Park, Dong Ii; Hisamatsu, Tadakazu; Chen, Minhu; Ng, Siew Chien; Ooi, Choon Jin; Wei, Shu Chen; Banerjee, Rupa; Hilmi, Ida Normiha; Jeen, Yoon Tae; Han, Dong Soo; Kim, Hyo Jong; Ran, Zhihua; Wu, Kaichun; Qian, Jiaming; Hu, Pin-Jin; Matsuoka, Katsuyoshi; Andoh, Akira; Suzuki, Yasuo; Sugano, Kentaro; Watanabe, Mamoru; Hibi, Toshifumi; Puri, Amarender S; Yang, Suk-Kyun

2018-01-01

Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asian Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection, and prevention of latent TB infection and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised two parts: (i) risk of TB infection during anti-TNF therapy and (ii) screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity.

PubMed

Gomes, Marcelo N; Braga, Rodolpho C; Grzelak, Edyta M; Neves, Bruno J; Muratov, Eugene; Ma, Rui; Klein, Larry L; Cho, Sanghyun; Oliveira, Guilherme R; Franzblau, Scott G; Andrade, Carolina Horta

2017-09-08

New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17-20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 μM and <10 μM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11-545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The ethanolic extract of ashitaba stem (Angelica keskei [Miq.] Koidz) as future antituberculosis

PubMed Central

Kusuma, Sri Agung Fitri; Iskandar, Yoppi; Dewanti, Mutiara Ayu

2018-01-01

Considering the easy contagion of tuberculosis (TB) disease spread and the emergence of multidrug-resistant TB, which directly impacts the failure of therapeutic goals and mortality rates increasing, TB disease control remains to be the main concern of continuous health development effort. Therefore, the discovery of new TB drug is needed. This research assessed the new natural anti-TB drug from the ethanolic extract of Angelica keiskei stem obtained from Lombok, Indonesia. The objectives of this study were to evaluate the sensitivity of Mycobacterium tuberculosis (Mtb) H37Rv strain to A. keiskei stem extract and to determine its minimum inhibitory concentration (MIC). The extraction methods of A. keiskei stem were done using a maceration method. In addition to phytochemical screening and water content analysis using standard method, the phytochemical parameters were analyzed by thin-layer chromatography. Ethanolic extract of A. keiskei stem was assayed for their Mtb inhibitory activity using the proportion method. The phytochemical analysis result showed that the secondary metabolites contain in the extract were flavonoid, polyphenol, tannin, monoterpenoid and sesquiterpen, quinon, and saponin. The anti-TB test result showed the active activity of ethanolic extract of A. keiskei against Mtb H37Rv strain with MIC ranging from 6% to 8% w/v. In conclusion, ethanolic extract of A. keiskei is a prospective natural anti-TB for the future. PMID:29441323

The development of new phosphors of Tb3+/Eu3+ co-doped Gd3Al5O12 with tunable emission

NASA Astrophysics Data System (ADS)

Teng, Xin; Wang, Wenzhi; Cao, Zhentao; Li, Jinkai; Duan, Guangbin; Liu, Zongming

2017-07-01

The gadolinium aluminum garnets Gd3Al5O12 (GdAG) activated with Tb3+/Eu3+ were successfully prepared via co-precipitation method at 1500 °C in this work. The crystal structure stabilization, elements analysis, microphotograph, PL/PLE spectra, decay behavior and quantum efficiency were discussed in detail. The metastable GdAG compounds been effectively stabilized by doping with smaller 10 at.% Tb3+, which then allows the development of new phosphors of (Gd0.9-xTb0.1Eux)3Al5O12 (GdAG:Tb3+/Eu3+, x = 0-0.03) for opto-functionality explorations. The PLE/PL spectra displays that the strongest PLE peak was located at ∼276 nm, which overlaps the 8S7/2 → 6IJ transition of Gd3+. Under 276 nm excitation, the phosphors exhibited both Tb3+ and Eu3+ emissions at 548 nm (green, 5D4 → 7F5 transition of Tb3+) and 592 nm (orange-red, 5D0 → 7F1 transition of Eu3+), respectively. The emission intensities of Tb3+ and Eu3+ remarkably varied with the Eu3+ incorporation. As a consequence, the emission color can be readily tuned from approximately green to orange-red. Fluorescence decay analysis found that the lifetime for the Tb3+ emission rapidly decreased conforming to the Tb3+ → Eu3+ energy transfer, and the energy transfer efficiency was calculated. Owing to the Gd3+ → Eu3+ and Gd3+ → Tb3+ energy transfer, the emission intensities of Tb3+ and Eu3+ in (Gd0.9-xTb0.1Eux)AG phosphor were higher than (Y0.87Tb0.1Eu0.03)AG and (Lu0.87Tb0.1Eu0.03)AG system. The (Gd0.9-xTb0.1Eux)AG garnet phosphors developed in this work may serve as a new type of phosphor which hopefully meets the requirements of various lighting and optical display applications.

Tuberculosis vaccines: time to think about the next generation.

PubMed

Kaufmann, Stefan H E

2013-04-01

Efforts over the last 2 decades have led to a rich research and development pipeline of tuberculosis (TB) vaccines. Although none of the candidates has successfully completed the clinical trial pipeline, many are under advanced clinical assessment. These vaccines aim at prevention of active TB, with most of them being considered for preexposure with recent additions for postexposure or multistage administration. A few therapeutic vaccines are under clinical assessment, as well. Preexposure vaccination with the licensed TB vaccine BCG prevents severe forms of TB in children but not in adolescents and adults. The current vaccine pipeline does not include strategies which prevent or eliminate infection with the causative agent Mycobacterium tuberculosis (Mtb). Rather in a best-case scenario, they are quantitatively superior to BCG in preventing active TB over prolonged periods of time, ideally lifelong in the face of latent Mtb infection. Qualitatively superior vaccines should be capable of preventing or eliminating Mtb infection, in this way eliminating the risk of TB reactivation. The time is now ripe to exploit radically new strategies to achieve this goal. Copyright © 2013. Published by Elsevier Ltd.

The association between sterilizing activity and drug distribution into tuberculosis lesions

PubMed Central

Prideaux, Brendan; Via, Laura E.; Zimmerman, Matthew D.; Eum, Seokyong; Sarathy, Jansy; O’Brien, Paul; Chen, Chao; Kaya, Firat; Weiner, Danielle M.; Chen, Pei-Yu; Song, Taeksun; Lee, Myungsun; Shim, TaeSun; Cho, Jeong Su; Kim, Wooshik; Cho, Sang Nae; Olivier, Kenneth N.; Barry, Clifton E.; Dartois, Véronique

2015-01-01

Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a MALDI mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside1. In contrast, moxifloxacin which is active in vitro against persisters, a sub-population of Mycobacterium tuberculosis that persists in specific niches under drug pressure, and achieved treatment shortening in mice2, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We also suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration contributes to treatment outcome has wide implications for TB. PMID:26343800

Naphthoquinones isolated from Diospyros anisandra exhibit potent activity against pan-resistant first-line drugs Mycobacterium tuberculosis strains.

PubMed

Uc-Cachón, Andrés Humberto; Borges-Argáez, Rocío; Said-Fernández, Salvador; Vargas-Villarreal, Javier; González-Salazar, Francisco; Méndez-González, Martha; Cáceres-Farfán, Mirbella; Molina-Salinas, Gloria María

2014-02-01

The recent emergence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) Mycobacterium tuberculosis (MTB) strains have further complicated the control of tuberculosis (TB). There is an urgent need of new molecules candidates to be developed as novel, active, and less toxic anti-tuberculosis (anti-TB) drugs. Medicinal plants have been an excellent source of leads for the development of drugs, particularly as anti-infective agents. In previous studies, the non-polar extract of Diospyros anisandra showed potent anti-TB activity, and three monomeric and five dimeric naphthoquinones have been obtained. In this study, we performed bioguided chemical fractionation and the isolation of eight naphthoquinones from D. anisandra and their evaluation of anti-TB and cytotoxic activities against mammalian cells. The n-hexane crude extract from the stem bark of the plant was obtained by maceration and liquid-liquid fractionation. The isolation of naphthoquinones was carried out by chromatographic methods and identified by gas chromatography and mass spectroscopy data analysis. Anti-TB activity was evaluated against two strains of MTB (H37Rv) susceptible to all five first-line anti-TB drugs and a clinical isolate that is resistant to these medications (pan-resistant, CIBIN 99) by measuring the minimal inhibitory concentration (MIC). Cytotoxicity of naphthoquinones was estimated against two mammalian cells, Vero line and primary cultures of human peripheral blood mononuclear (PBMC) cells, and their selectivity index (SI) was determined. Plumbagin and its dimers maritinone and 3,3'-biplumbagin showed the strongest activity against both MTB strains (MIC = 1.56-3.33 μg/mL). The bioactivity of maritinone and 3,3'-biplumbagin were 32 times more potent than rifampicin against the pan-resistant strain, and both dimers showed to be non-toxic against PBMC and Vero cells. The SI of maritinone and 3,3'-biplumbagin on Vero cells was 74.34 and 194.11 against sensitive and pan-resistant MTB strains, respectively. Maritinone and 3,3'-biplumbagin possess a very interesting potential for development as new drugs against M. tuberculosis, mainly resistant profile strains. Copyright © 2013 Elsevier Ltd. All rights reserved.

European union standards for tuberculosis care.

PubMed

Migliori, G B; Zellweger, J P; Abubakar, I; Ibraim, E; Caminero, J A; De Vries, G; D'Ambrosio, L; Centis, R; Sotgiu, G; Menegale, O; Kliiman, K; Aksamit, T; Cirillo, D M; Danilovits, M; Dara, M; Dheda, K; Dinh-Xuan, A T; Kluge, H; Lange, C; Leimane, V; Loddenkemper, R; Nicod, L P; Raviglione, M C; Spanevello, A; Thomsen, V Ø; Villar, M; Wanlin, M; Wedzicha, J A; Zumla, A; Blasi, F; Huitric, E; Sandgren, A; Manissero, D

2012-04-01

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Impaired IFN-α-mediated signal in dendritic cells differentiates active from latent tuberculosis.

PubMed

Parlato, Stefania; Chiacchio, Teresa; Salerno, Debora; Petrone, Linda; Castiello, Luciano; Romagnoli, Giulia; Canini, Irene; Goletti, Delia; Gabriele, Lucia

2018-01-01

Individuals exposed to Mycobacterium tuberculosis (Mtb) may be infected and remain for the entire life in this condition defined as latent tuberculosis infection (LTBI) or develop active tuberculosis (TB). Among the multiple factors governing the outcome of the infection, dendritic cells (DCs) play a major role in dictating antibacterial immunity. However, current knowledge on the role of the diverse components of human DCs in shaping specific T-cell response during Mtb infection is limited. In this study, we performed a comparative evaluation of peripheral blood circulating DC subsets as well as of monocyte-derived Interferon-α DCs (IFN-DCs) from patients with active TB, subjects with LTBI and healthy donors (HD). The proportion of circulating myeloid BDCA3+ DCs (mDC2) and plasmacytoid CD123+ DCs (pDCs) declined significantly in active TB patients compared to HD, whereas the same subsets displayed a remarkable activation in LTBI subjects. Simultaneously, the differentiation of IFN-DCs from active TB patients resulted profoundly impaired compared to those from LTBI and HD individuals. Importantly, the altered developmental trait of IFN-DCs from active TB patients was associated with down-modulation of IFN-linked genes, marked changes in molecular signaling conveying antigen (Ag) presentation and full inability to induce Ag-specific T cell response. Thus, these data reveal an important role of IFN-α in determining the induction of Mtb-specific immunity.

Impaired IFN-α-mediated signal in dendritic cells differentiates active from latent tuberculosis

PubMed Central

Parlato, Stefania; Chiacchio, Teresa; Salerno, Debora; Petrone, Linda; Castiello, Luciano; Romagnoli, Giulia; Canini, Irene; Goletti, Delia; Gabriele, Lucia

2018-01-01

Individuals exposed to Mycobacterium tuberculosis (Mtb) may be infected and remain for the entire life in this condition defined as latent tuberculosis infection (LTBI) or develop active tuberculosis (TB). Among the multiple factors governing the outcome of the infection, dendritic cells (DCs) play a major role in dictating antibacterial immunity. However, current knowledge on the role of the diverse components of human DCs in shaping specific T-cell response during Mtb infection is limited. In this study, we performed a comparative evaluation of peripheral blood circulating DC subsets as well as of monocyte-derived Interferon-α DCs (IFN-DCs) from patients with active TB, subjects with LTBI and healthy donors (HD). The proportion of circulating myeloid BDCA3+ DCs (mDC2) and plasmacytoid CD123+ DCs (pDCs) declined significantly in active TB patients compared to HD, whereas the same subsets displayed a remarkable activation in LTBI subjects. Simultaneously, the differentiation of IFN-DCs from active TB patients resulted profoundly impaired compared to those from LTBI and HD individuals. Importantly, the altered developmental trait of IFN-DCs from active TB patients was associated with down-modulation of IFN-linked genes, marked changes in molecular signaling conveying antigen (Ag) presentation and full inability to induce Ag-specific T cell response. Thus, these data reveal an important role of IFN-α in determining the induction of Mtb-specific immunity. PMID:29320502

Evaluation of a New IFN-γ Release Assay for Rapid Diagnosis of Active Tuberculosis in a High-Incidence Setting.

PubMed

Li, Gen; Li, Feng; Zhao, Hui-Min; Wen, Han-Li; Li, Hai-Cong; Li, Chun-Ling; Ji, Ping; Xu, Peng; Wu, Kang; Hu, Zhi-Dong; Lu, Shui-Hua; Lowrie, Douglas B; Lv, Jian-Xin; Fan, Xiao-Yong

2017-01-01

Blood-based interferon-gamma (IFN-γ) release assays (IGRAs) have been proven to be useful in the diagnosis of Mycobacterium tuberculosis ( Mtb ) infection. However, IGRAs have not been recommended for clinical practice in most low-income settings due to cost-intensive limitations and shortage of clinical data available. The established T-SPOT. TB assay containing Mtb -specific antigens ESAT-6 and CFP10 are widely used for immunodiagonsis of Mtb infection, but the high cost is one of the restricting factors against its clinical application in the developing countries. More recently, a cost-saving IGRA assay, TS-SPOT, was approved in China. This new assay contains an additional antigen Rv3615c. Rv3615c contains broadly recognized CD4 + and CD8 + epitopes, and T-cell responses to Rv3615c are as specific for Mtb infection as the responses to ESAT-6 and CFP10 in both Mtb -infected humans and M. bovis -infected cattle. Therefore, we assessed the likely effect of inclusion of Rv3615c as stimulus besides ESAT-6 and CFP10 in an IGRA assay and evaluated the performance of TS-SPOT for diagnosis of Mtb infection and active TB compared with T-SPOT. TB . We tested 155 active TB patients, 90 non-TB lung disease patients, and 55 healthy individuals. The results presented an improved positive rate for diagnosis of active TB and Mtb infection, that could be attributable to inclusion of Rv3615c in the mixture of stimulatory antigens. The diagnostic efficiency of TS-SPOT assay for active TB was as follows: sensitivity 80.00%, specificity 83.45%, positive predictive value (PPV) 83.78%, negative predictive value (NPV) 83.45%, positive likelihood ratio (LR+) 4.83, and negative likelihood ratio (LR-) 0.24. The results were similar to those of T-SPOT. TB , with an excellent agreement (κ = 0.91, 95% CI: 0.85-0.95) being observed between these two assays. The sensitivities of the TS-SPOT assay varied for patients with different forms of active TB, with the highest sensitivity for patients with culture-positive pulmonary TB (92.16%) and the lowest for those with tuberculosis meningitis (50.00%). Taken together, the current evidence indicates that this new TS-SPOT assay is a useful adjunct to the current tests for rapid diagnosis of active TB and Mtb infection in low-income and high-incidence settings due to its characteristics of cost-effectiveness and high-quality.

In vitro cytotoxicity of CD8+ T cells in multi-drug-resistant tuberculosis. A preliminary report.

PubMed

Sada-Ovalle, Isabel; Torre-Bouscoulet, Luis; Valdez-Vázquez, Rafael; Lascurain, Ricardo

2009-05-01

Specific CD8+ T-cell cytotoxicity has been recognized as being involved in the elimination of drug-susceptible tuberculosis (DS-TB). Given that there is currently no information on the cytotoxic effector functions of CD8+ T cells in multi-drug-resistant tuberculosis (MDR-TB), our objective was to analyse the cytotoxic activity, both basal and stimulated, of CD8+ T cells from MDR-TB patients and compare it with that of DS-TB patients, as well as purified protein derivative (PPD)+ and PPD- subjects. Cytotoxic activity of CD8+ T cells from MDR-TB patients, DS-TB patients, PPD+ and PPD- subjects was measured by a colorimetric assay, using H37Rv culture filtrate protein as the antigenic stimulus. Twenty-eight subjects were studied (7 MDR-TB patients, 7 DS-TB patients, 7 PPD+ subjects and 7 PPD- subjects). In the presence of the antigenic stimulus, the cytotoxic activity of CD8+ T cells from MDR-TB patients (% lysis) increased from 6.7% to 59.6% (P < 0.001). In DS-TB patients lysis increased from 3.2% to 22.5% (P < 0.001), whereas in PPD+ subjects it increased from 2.7% to 12.0% (P < 0.001) and in PPD- subjects from 1.3% to 3.2% (P < 0.001). Basal cytotoxic activity was significantly higher for MDR-TB patients than PPD+ and PPD- subjects (P = 0.003), but not compared with that for DS-TB patients (P = 0.05). Stimulated cytotoxic activity was highest for MDR-TB patients. CD8+ T cells from MDR-TB patients showed an exaggerated cytotoxic activity after antigenic stimulation. Further studies are required to elucidate the role of this response in the immunopathogenesis of MDR-TB.

[Tuberculosis and its control--lessons from the past and future prospect].

PubMed

Shimao, Tadao

2005-06-01

Koch R reported the discovery of tubercle bacilli on March 24, 1882, and the numbers of death from phthisis were collected in the vital statistics from the latter half of 1883 in Japan. Tuberculosis death was officially adopted in the Japanese vital statistics from 1899, and there was certain disagreement existed between the numbers of death from TB and phthisis in 1899, the analysis on the trend of TB in Japan was done based on TB death. Trend of TB in Japan in the past 100 years could be divided into five phases. In phase 1 (1899-1918), TB mortality had increased with the first industrialization of Japan with main focus on the weaving industry. During this period, TB mortality of female was higher than that of male and then major victims of TB were young girls born from 1890 to 1925. In phase 2 (1918-1930), TB mortality decreased through excess death of TB cases by the influenza pandemic in 1918. This decline due to influenza pandemic was seen all over the world, and in the European countries and the U.S., the decline continued up to 1945 while in Japan, TB had increased again in the phase 3 (1930-1945) mainly due to second industrialization with main focus on heavy industry and the impact of quasi-war and war conditions. In phase 4 (1945-mid 1970s), TB started to decline fast due to the excess death of TB cases during the World War II and then, the application of modern TB control started from early 1950s. In phase 5 (from mid 1970s until now), decline of TB has showed down. Increase or slowdown of TB decline was seen nearly all countries of the world, however, its causes were different from country to country. In case of Japan, slowdown was caused by the rapid ageing of the population, in developing countries mainly by the impact of HIV epidemic and in industrialized countries, mainly by the migration of the population and partly by the HIV epidemic. Contribution of phthisiology in Japan to the global progress of phthisiology could be summarized as follows: elucidation of the pathogenesis of TB when TB was highly prevalent in Japan by high incidence of TB from primarily infected youth, the development of mass screening for TB using radiophotography technique developed in Japan, completion of the interpretation method of chest X-ray findings, first success in the mass production of freeze-dried BCG vaccine in the world, the first implementation of the TB prevalence survey using random sampling method in 1953, and the development of a new drug for TB, kanamycin. Phthisiology also contributed to the progress of international health. As the objective index to measure the magnitude of TB problem, the concept of annual risk of TB infection (ARTI) was introduced by Sutherland and Styblo, and by using ARTI, the epidemiological situation of TB could be divided into 3 categories; high prevalence country with ARTI above 1%, low prevalence country below 0.05-0.1%, and middle prevalence country inbetween. To reduce the burden of TB in high prevalence countries, so-called DOTS strategy of TB control was introduced and has been applied in most developing countries, and the gap between high and low prevalence countries has reduced in the past decade. Cooperation in global TB control has also been done actively from the government and NGOs of industrialized countries under the strong leadership of WHO. For the success of TB control, the transmission of tubercle bacilli in a community should be cut either infection, onset of TB or the progress of TB. Prevention of TB infection could be achieved by the early detection of TB cases and their cure by the treatment. To encourage early visit to doctors for those with symptoms suggesting TB and adequate examinations at medical institutions for these persons would be a major tool of early detection of TB cases in Japan in the future. In addition, there is no doubt to intensify contacts examinations and source investigations. It is hoped to elucidate recent pathogenesis of TB by applying new technologies such as QFT and RFLP. Prevention of onset of TB will be focused on the preventive use of TB drugs, however, development of new vaccine better than BCG is also encouraged for the developing countries where the risk of TB infection is remained high. TB is now a curable disease, and the duration of treatment has been shortened to 6 months. If new more potent TB drugs were developed, and the total duration of treatment could be shortened, the global TB control could be done much more easily, and also most MDRTB cases could be cured. Otsuka Pharmaceutical Company is now developing a new potent drug which has no cross resistance with existing TB drugs. This new drug is now on the clinical trial phase II, and it is hoped that Japan can make another great contribution to the global TB control. It is my sincere wish that the government continues to assist the research to develop new TB drugs and new technologies used in TB control, and in future, if it is needed to change the current policy of TB control, a new policy should be tried in a pilot area before its introduction on national level. The Japanese Society for TB is a key organization in developing further research and the training of new personnel engaging in TB research and control, and I sincerely hope further development of the Society.

Tuberculosis after liver transplantation in a large center in New York City: QuantiFERON® -TB Gold-based pre-transplant screening performance and active tuberculosis post-transplant.

PubMed

Hand, Jonathan; Sigel, Keith; Huprikar, Shirish; Hamula, Camille; Rana, Meena

2018-04-01

Pre-transplant screening for latent tuberculosis infection (LTBI) is a complex consideration that varies by institution. Inconsistent performance of interferon-gamma release assay (IGRA) further complicates screening. Data regarding LTBI screening outcomes and test characteristics in a large, foreign-born pre-transplant population within the United States are limited. In this retrospective study, patients who received QuantiFERON ® -TB Gold (QFT) prior to liver transplantation (LT) were included. Characteristics of patients were compared by QFT result, and predictors of indeterminate results were evaluated. Similar comparisons were performed between patients who developed active TB and those who did not. Of 148 patients screened, the rate of positive, indeterminate, and negative testing was 13.5% (20/148), 27% (40/148), and 59% (88/148), respectively. An indeterminate QFT result was more than 16 times more likely in patients with a Model for End-stage Liver Disease score >25 (odds ratio [OR] 16.7; 95% confidence interval [CI], 2.1-132.0; P = .008) and more than 4 times when performed in our institution's lab compared with commercial lab (OR 4.1; 95% CI, 1.34-12.44; P = .013). The overall TB incidence was 1102/100 000 transplant cases. No patient who developed active TB had a positive QFT. All were born outside of the United States (P = .06) and had pre-transplantation chest imaging demonstrating granulomatous disease (P = .006). Our experience further highlights the challenges of LTBI screening prior to LT and suggests that QFT may be a poor predictor of active TB in higher risk pre-transplant populations. Candidates should be screened as early as possible to optimize QFT performance, and local epidemiological data should be used to create institution-specific screening protocols in areas with large populations from TB-endemic regions. Management should consider TB risk factors, QFT, and imaging instead of reliance on QFT testing alone. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Why the tuberculosis incidence rate is not falling in New Zealand.

PubMed

Das, Dilip; Baker, Michael; Venugopal, Kamalesh; McAllister, Susan

2006-10-13

To assess the role of migration from high-incidence countries, HIV/AIDS infection, and prevalence of multi-drug resistant organisms as contributors to tuberculosis (TB) incidence in New Zealand (NZ) relative to ongoing local transmission and reactivation of disease. TB notification data and laboratory data for the period 1995 to 2004 and population data from the 1996 and 2001 Census were used to calculate incidence rates of TB by age and ethnicity, country of birth (distinguishing high and low -incidence countries), and interval between migration and onset of disease. Published reports of multi-drug-resistant TB for the period 1995 to 2004 were reviewed. Anonymous HIV surveillance data held by AIDS Epidemiology Group were matched with coded and anonymised TB surveillance data to measure the extent of HIV/AIDS coinfection in notified TB cases. Migration of people from high-TB incidence countries is the main source of TB in NZ. Of those who develop TB, a quarter does so within a year of migration, and a quarter of this group (mainly refugees) probably enter the country with pre-existing disease. Rates of local TB transmission and reactivation of old disease are declining steadily for NZ-born populations, except for NZ-born Maori and Pacific people under 40. HIV/AIDS and multi-drug-resistant organisms are not significant contributors to TB incidence in NZ and there is no indication that their role is increasing. TB incidence is not decreasing in NZ mainly due to migration of TB infected people from high-incidence countries and subsequent development of active disease in some of them in NZ. This finding emphasises the importance of regional and global TB control initiatives. Refugees and migrants are not acting as an important source of TB for most NZ-born populations. Those caring for them should have a high level of clinical suspicion for TB.

Performance of the QuantiFERON-TB Gold Assay Among HIV-infected Children With Active Tuberculosis in France.

PubMed

Hormi, Myriam; Guérin-El Khourouj, Valérie; Pommelet, Virginie; Jeljeli, Mohamed; Pédron, Béatrice; Diana, Jean-Sébastien; Faye, Albert; Sterkers, Ghislaine

2018-04-01

Data regarding the use of QuantiFERON to assist the diagnosis of active tuberculosis (TB) in HIV-infected children are limited, especially in countries with low incidence of TB/HIV coinfection. QuantiFERON results were analyzed in 63 HIV-infected children who presented to our hospital in Paris, France. Seventeen HIV-uninfected children with active TB (4 culture-confirmed) were included for comparison. The 63 HIV-infected children (median age: 11 yr) had 113 QuantiFERON tests. Thirty-four (54%) were born in sub-Saharan Africa. Vertical HIV transmission was documented for 50 of 52 (96%) and stage III HIV-infection for 30 of 50 children (60%). Over the study period, active TB was diagnosed in 7 of 63 HIV-infected children (3 culture-confirmed). Additional ongoing or previous opportunistic infections were present in 4 of 7. QuantiFERON results were positive in 2 of 7 HIV-infected children with active TB (sensitivity: 29%) and 16 of 17 HIV-uninfected children with active TB (sensitivity: 94%). At initial QuantiFERON testing of the 63 HIV-infected children, 8 (13%) had positive results (1, active TB; 5, latent TB; 2, previous TB) and 51 (81%) had negative results. Of 33 children with repeat testing after an initially positive or negative result, the only change was one conversion from a negative to a positive result at the onset of active TB. The 4 children (6%) with indeterminate quantiFERON results had a concomitant opportunistic infection. Results of repeat testing after clinical stabilization were negative in all 4. QuantiFERON testing performed poorly for active TB diagnosis in this series of children with advanced HIV infection.

Status of nosocomial tuberculosis transmission prevention in hospitals in Thailand.

PubMed

Unahalekhaka, Akeau; Lueang-a-papong, Suchada; Chitreecheur, Jittaporn

2014-03-01

A national survey was conducted during July to September 2009 to determine tuberculosis (TB) prevention activities, problems, and support needed of Thai hospitals. Ninety-seven percent of hospitals established TB isolation policy, 96.3% provided guidelines for caring of TB patients, 95% and 91.8% provided prevention of TB transmission and environmental management guideline, and 92.6% established screening system for TB in the outpatient department (OPD). A half of hospitals had problems with isolation rooms and difficulties in screening TB cases in the OPD. Support needed included consultation on structure and ventilation systems, personnel training, national TB prevention, and TB screening guideline. Strengthening TB prevention activities, providing expert consultation, and national guidelines may help hospitals improve their TB prevention activities. Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.

Persistent latent tuberculosis reactivation risk in United States immigrants.

PubMed

Walter, Nicholas D; Painter, John; Parker, Matthew; Lowenthal, Phillip; Flood, Jennifer; Fu, Yunxin; Asis, Redentor; Reves, Randall

2014-01-01

Current guidelines limit latent tuberculosis infection (LTBI) evaluation to persons in the United States less than or equal to 5 years based on the assumption that high TB rates among recent entrants are attributable to high LTBI reactivation risk, which declines over time. We hypothesized that high postarrival TB rates may instead be caused by imported active TB. Estimate reactivation and imported TB in an immigrant cohort. We linked preimmigration records from a cohort of California-bound Filipino immigrants during 2001-2010 with subsequent TB reports. TB was likely LTBI reactivation if the immigrant had no evidence of active TB at preimmigration examination, likely imported if preimmigration radiograph was abnormal and TB was reported less than or equal to 6 months after arrival, and likely reactivation of inactive TB if radiograph was abnormal but TB was reported more than 6 months after arrival. Among 123,114 immigrants, 793 TB cases were reported. Within 1 year of preimmigration examination, 85% of TB was imported; 6 and 9% were reactivation of LTBI and inactive TB, respectively. Conversely, during Years 2-9 after U.S. entry, 76 and 24% were reactivation of LTBI and inactive TB, respectively. The rate of LTBI reactivation (32 per 100,000) did not decline during Years 1-9. High postarrival TB rates were caused by detection of imported TB through active postarrival surveillance. Among immigrants without active TB at baseline, reported TB did not decline over 9 years, indicating sustained high risk of LTBI reactivation. Revised guidelines should support LTBI screening and treatment more than 5 years after U.S. arrival.

Comparative field efficacy of newly developed formulations of larvicides against Aedes aegypti (L.) (Diptera: Culicidae).

PubMed

Thavara, Usavadee; Tawatsin, Apiwat; Chompoosri, Jakkrawarn; Bhakdeenuan, Payu; Khamsawads, Chayada; Sangkitporn, Somchai; Siriyasatien, Padet; Asavadachanukorn, Preecha; Boonmuen, Saibua; Mulla, Mir S

2013-09-01

Aedes aegypti (L.) is known as vector of dengue and chikungunya fever. Larvicides are used to control this vector. We evaluated the efficacy of newly developed formulations of larvicides to control Ae. aegypti under field conditions for 24 weeks post single application. Mosdop P and Mosdop TB containing diflubenzuron (2% and 40 mg/tablet, respectively) as the active ingredient, were applied at a dosage of 0.1 mg a.i./1 and Mosquit TB10, Mosquit TB100 and Temecal containing temephos (1%, 10% and 1%, respectively) as the active ingredient were applied at a dosage of 1 mg active ingredent (a.i.) to 200 liter water storage jars. Two water regimens were used in the jars: in one regimen the jar was kept full of water all the time and in the other regimen a full jar had half the volume removed and refilled weekly. The larvicidal efficacy was reported as the level of inhibition of emergence (IE%) calculated based on the pupal skins in the jars versus the original number of larvae added. Mosdop P, Mosdop TB, Mosquit TB10, Mosquit TB100 and Temecal showed complete larvicidal efficacy (100% IE) in the constantly full jars for 16, 17, 14, 20 and 13 weeks posttreatment, respectively; in the jars where half the volum of water was replaced weekly, the larvicides had complete larvicidal efficacy (100% IE) for 19, 20, 17, 24 and 15 weeks post-treatment, respectively. The five larvicide regimens evaluated in this study are effective for controlling Ae. aegypti larvae.

Mycobacterial lipolytic enzymes: a gold mine for tuberculosis research.

PubMed

Dedieu, L; Serveau-Avesque, C; Kremer, L; Canaan, S

2013-01-01

Tuberculosis (TB) is one of the deadliest infectious diseases worldwide with a strong impact in developing countries. Mycobacterium tuberculosis, the etiological agent of TB, has a high capacity to evade the host immune system and establish a chronic, asymptomatic and latent infection. In a latent TB infection, persistent bacilli are present in a non-replicating dormant state within host granulomas. During reactivation, bacilli start replicating again leading to an active TB infection that can be highly contagious. Mycobacterial lipids and lipolytic enzymes are thought to play important physiological roles during dormancy and reactivation. The role of lipolytic enzymes in the physiology of M. tuberculosis and physiopathology of the disease will be discussed in this review, with an emphasis on the secreted or cell wall-associated, surface exposed lipolytic enzymes characterized to date. Studies on the localization, enzymatic activity and immunological properties of these enzymes highlighted their possible usefulness as new diagnostic markers in the fight against TB. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Prevalence of latent tuberculosis infection in healthcare workers at a hospital in Naples, Italy, a low-incidence country.

PubMed

Lamberti, Monica; Muoio, Mariarosaria; Arnese, Antonio; Borrelli, Sharon; Di Lorenzo, Teresa; Garzillo, Elpidio Maria; Signoriello, Giuseppe; De Pascalis, Stefania; Coppola, Nicola; Nienhaus, Albert

2016-01-01

Healthcare workers (HCWs) are at higher risk than the general population of contracting tuberculosis (TB). Moreover, although subjects with latent TB infection (LTBI) are asymptomatic and are not infectious, they may eventually develop active disease. Thus, a fundamental tool of TB control programs for HCWs is the screening and treatment of LTBI. From January 2014 to January 2015, hospital personnel at Azienda Ospedaliera Universitaria, Naples, Italy, were screened for TB. To this end, a tuberculin skin test (TST) was administered as an initial examination, unless when contraindicated, in which case the QuantiFERON® TB-Gold (QFT) assay was performed. Moreover, QFT was carried out on all TST-positive cases to confirm the initial result. Of 628 personnel asked to participate, 28 (4.5%) denied consent, 533 were administered TST as the baseline examination, and 67 were tested only with QFT. In the TST group, 73 (13.2%) individuals were found positive, 418 (78.4%) were negative, and 42 (7.9%) were absent for the reading window; QFT confirmed the result in 39 (53.4%) TST-positive individuals. In the QFT-only group, 44 (65.7%) individuals were found positive. All TST- and/or QFT-positive subjects were referred for chest X-ray and examination by an infectious diseases specialist. None were found to have active TB, and were thus diagnosed with LTBI. Although Italy is a low-incidence country regarding TB, our findings suggest that the prevalence of LTBI in HCWs may be relatively high. As a result, active screening for TB and LTBI is needed for these workers.

Fibroblast activation protein (FAP) as a novel metabolic target.

PubMed

Sánchez-Garrido, Miguel Angel; Habegger, Kirk M; Clemmensen, Christoffer; Holleman, Cassie; Müller, Timo D; Perez-Tilve, Diego; Li, Pengyun; Agrawal, Archita S; Finan, Brian; Drucker, Daniel J; Tschöp, Matthias H; DiMarchi, Richard D; Kharitonenkov, Alexei

2016-10-01

Fibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on metabolic regulation in mice. To address this question we evaluated the pharmacology of TB in various mouse models including those deficient in FGF21, GLP1 and GIP signaling. We also studied the ability of FAP to process FGF21 in vitro and TB to block FAP enzymatic activity. TB administration to diet-induced obese (DIO) animals led to profound decreases in body weight, reduced food consumption and adiposity, increased energy expenditure, improved glucose tolerance and insulin sensitivity, and lowered cholesterol levels. Total and intact plasma FGF21 were observed to be elevated in TB-treated DIO mice but not lean animals where the metabolic impact of TB was significantly attenuated. Furthermore, and in stark contrast to naïve DIO mice, the administration of TB to obese FGF21 knockout animals demonstrated no appreciable effect on body weight or any other measures of metabolism. In support of these results we observed no enzymatic degradation of human FGF21 at either end of the protein when FAP was inhibited in vitro by TB. We conclude that pharmacological inhibition of FAP enhances levels of FGF21 in obese mice to provide robust metabolic benefits not observed in lean animals, thus validating this enzyme as a novel drug target for the treatment of obesity and diabetes.

Southeast Asian Medicinal Plants as a Potential Source of Antituberculosis Agent

PubMed Central

Sanusi, Shuaibu Babaji; Mohamed, Maryati; Mainasara, Muhammad Murtala

2017-01-01

Despite all of the control strategies, tuberculosis (TB) is still a major cause of death globally and one-third of the world's population is infected with TB. The drugs used for TB treatment have drawbacks of causing adverse side effects and emergence of resistance strains. Plant-derived medicines have since been used in traditional medical system for the treatment of numerous ailments worldwide. There were nine major review publications on antimycobacteria from plants in the last 17 years. However, none is focused on Southeast Asian medicinal plants. Hence, this review is aimed at highlighting the medicinal plants of Southeast Asian origin evaluated for anti-TB. This review is based on literatures published in various electronic database. A total of 132 plants species representing 45 families and 107 genera were reviewed; 27 species representing 20.5% exhibited most significant in vitro anti-TB activity (crude extracts and/or bioactive compounds 0–<10 µg/ml). The findings may motivate various scientists to undertake the project that may result in the development of crude extract that will be consumed as complementary or alternative TB drug or as potential bioactive compounds for the development of novel anti-TB drug. PMID:29081822

Epidemiology and outcome of tuberculosis in immunocompromised patients.

PubMed

Metry, Abdul Massiah; Al Salmi, Issa; Al-Abri, Seif; Al Ismaili, Faisal; Al Mahrouqi, Yaqoub; Hola, Alan; Shaheen, Faissal A M

2017-01-01

The United States Renal Data System showed 1.2% and 1.6% incidences of tuberculosis (TB) in patients on peritoneal dialysis and hemodialysis (HD), respectively. Kidney transplant (KTX) patients have higher rates. We studied the epidemiology and outcome of TB in patients with kidney dysfunction in a tertiary care hospital in the past decade. We examined data of patients with TB with and without kidney dysfunction from 2006 to 2015 through an electronic system. Statistical analysis was completed using Stata software, Chicago, IL, USA. We found 581 patients with active TB of whom 37 had renal dysfunction including chronic kidney disease, HD, and KTX. No difference was found in the prevalence, age, or gender predilection. The age ranged from 1 to 95 with a mean (standard deviation) of 38.6 (21.1) years. The incidence of TB is 3 per 100,000. The number of patients per year with active TB ranges from 52 to 128 and 3 to 4 in the general population and kidney dysfunction group, respectively. Sixty-five percent of patients with kidney dysfunction had pulmonary TB, 5% had pleurisy, and 30% had extrapulmonary TB. Eighty-four percent of patients with kidney dysfunction completed the course of treatment with 16% treatment failure and 0.4% developed multidrug-resistant TB; 8% were lost to follow-up and 8% died during the treatment period. This study showed no gender predilection for TB in the general population and immunocompromised. Duration of symptoms before diagnosis of TB was shorter in kidney dysfunction patients in comparison to the general population. TB cultures were the most positive tests whereas bronchoalveolar lavage and skin test were the least positive for detecting TB in the kidney dysfunction group. Improvement in registries and screening is required to enhance the capturing rate and detection among this group, as well as providing accurate data to health authorities and the public about the magnitude, future trends, treatments, and outcomes regarding TB in kidney dysfunction.

Host-Directed Therapeutics as a Novel Approach for Tuberculosis Treatment.

PubMed

Kim, Ye-Ram; Yang, Chul-Su

2017-09-28

Despite significant efforts to improve the treatment of tuberculosis (TB), it remains a prevalent infectious disease worldwide owing to the limitations of current TB therapeutic regimens. Recent work on novel TB treatment strategies has suggested that directly targeting host factors may be beneficial for TB treatment. Such strategies, termed host-directed therapeutics (HDTs), focus on host-pathogen interactions. HDTs may be more effective than the currently approved TB drugs, which are limited by the long durations of treatment needed and the emergence of drug-resistant strains. Targets of HDTs include host factors such as cytokines, immune checkpoints, immune cell functions, and essential enzyme activities. This review article discusses examples of potentially promising HDTs and introduces novel approaches for their development.

Predictive value of serum bradykinin and desArg9-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: A retrospective case series.

PubMed

Qian, Xu; Nguyen, Duc T M; Li, Yaojun; Lyu, Jianxin; Graviss, Edward A; Hu, Tony Y

2016-12-01

There is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg 9 -bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases. Nanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status. Serum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease. Our pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers of the host response both early and late in anti-TB treatment for both pulmonary and extrapulmonary TB patients. We will further exploit these host-response signatures in the future as biomarkers in combination with other clinical and microbiologic tools which may improve treatment efficacy and facilitate the development of host-directed therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Analogues of the Frog-skin Antimicrobial Peptide Temporin 1Tb Exhibit a Wider Spectrum of Activity and a Stronger Antibiofilm Potential as Compared to the Parental Peptide

NASA Astrophysics Data System (ADS)

Grassi, Lucia; Maisetta, Giuseppantonio; Maccari, Giuseppe; Esin, Semih; Batoni, Giovanna

2017-04-01

The frog skin-derived peptide Temporin 1Tb (TB) has gained increasing attention as novel antimicrobial agent for the treatment of antibiotic-resistant and/or biofilm-mediated infections. Nevertheless, such a peptide possesses a preferential spectrum of action against Gram-positive bacteria. In order to improve the therapeutic potential of TB, the present study evaluated the antibacterial and antibiofilm activities of two TB analogues against medically relevant bacterial species. Of the two analogues, TB_KKG6A has been previously described in the literature, while TB_L1FK is a new analogue designed by us through statistical-based computational strategies. Both TB analogues displayed a faster and stronger bactericidal activity than the parental peptide, especially against Gram-negative bacteria in planktonic form. Differently from the parental peptide, TB_KKG6A and TB_L1FK were able to inhibit the formation of Staphylococcus aureus biofilms by more than 50% at 12 μM, while only TB_KKG6A prevented the formation of Pseudomonas aeruginosa biofilms at 24 μM. A marked antibiofilm activity against preformed biofilms of both bacterial species was observed for the two TB analogues when used in combination with EDTA. Analysis of synergism at the cellular level suggested that the antibiofilm activity exerted by the peptide-EDTA combinations against mature biofilms might be due mainly to a disaggregating effect on the extracellular matrix in the case of S. aureus, and to a direct activity on biofilm-embedded cells in the case of P. aeruginosa. Both analogues displayed a low hemolytic effect at the active concentrations and, overall, TB_L1FK resulted less cytotoxic towards mammalian cells. Collectively, the results obtained demonstrated that subtle changes in the primary sequence of TB may provide TB analogues that, used alone or in combination with adjuvant molecules such as EDTA, exhibit promising features against both planktonic and biofilm cells of medically relevant bacteria.

Detection of a combination of serum IgG and IgA antibodies against selected mycobacterial targets provides promising diagnostic signatures for active TB

PubMed Central

Chegou, Novel N.; Kriel, Belinda; Jacobs, Ruschca; Kidd, Martin; Loxton, Andre G.; Kaempfer, Susanne; Singh, Mahavir; Walzl, Gerhard

2017-01-01

Immunoglobulin G (IgG) based tests for the diagnosis of active tuberculosis (TB) disease often show a lack of specificity in TB endemic regions, which is mainly due to a high background prevalence of LTBI. Here, we investigated the combined performance of the responses of different Ig classes to selected mycobacterial antigens in primary healthcare clinic attendees with signs and symptoms suggestive of TB. The sensitivity and specificity of IgA, IgG and/or IgM to LAM and 7 mycobacterial protein antigens (ESAT-6, Tpx, PstS1, AlaDH, MPT64, 16kDa and 19kDa) and 2 antigen combinations (TUB, TB-LTBI) in the plasma of 63 individuals who underwent diagnostic work-up for TB after presenting with symptoms and signs compatible with possible active TB were evaluated. Active TB was excluded in 42 individuals of whom 21 has LTBI whereas active TB was confirmed in 21 patients of whom 19 had a follow-up blood draw at the end of 6-month anti-TB treatment. The leading single serodiagnostic markers to differentiate between the presence or absence of active TB were anti-16 kDa IgA, anti-MPT64 IgA with sensitivity and specificity of 90%/90% and 95%/90%, respectively. The combined use of 3 or 4 antibodies further improved this performance to accuracies above 95%. After successful completion of anti-TB treatment at month 6, the levels of 16 kDa IgA and 16 kDa IgM dropped significantly whereas LAM IgG and TB-LTBI IgG increased. These results show the potential of extending investigation of anti-tuberculous IgG responses to include IgM and IgA responses against selected protein and non-protein antigens in differentiating active TB from other respiratory diseases in TB endemic settings. PMID:28415587

Detection of a combination of serum IgG and IgA antibodies against selected mycobacterial targets provides promising diagnostic signatures for active TB.

PubMed

Awoniyi, Dolapo O; Baumann, Ralf; Chegou, Novel N; Kriel, Belinda; Jacobs, Ruschca; Kidd, Martin; Loxton, Andre G; Kaempfer, Susanne; Singh, Mahavir; Walzl, Gerhard

2017-06-06

Immunoglobulin G (IgG) based tests for the diagnosis of active tuberculosis (TB) disease often show a lack of specificity in TB endemic regions, which is mainly due to a high background prevalence of LTBI. Here, we investigated the combined performance of the responses of different Ig classes to selected mycobacterial antigens in primary healthcare clinic attendees with signs and symptoms suggestive of TB. The sensitivity and specificity of IgA, IgG and/or IgM to LAM and 7 mycobacterial protein antigens (ESAT-6, Tpx, PstS1, AlaDH, MPT64, 16kDa and 19kDa) and 2 antigen combinations (TUB, TB-LTBI) in the plasma of 63 individuals who underwent diagnostic work-up for TB after presenting with symptoms and signs compatible with possible active TB were evaluated. Active TB was excluded in 42 individuals of whom 21 has LTBI whereas active TB was confirmed in 21 patients of whom 19 had a follow-up blood draw at the end of 6-month anti-TB treatment. The leading single serodiagnostic markers to differentiate between the presence or absence of active TB were anti-16 kDa IgA, anti-MPT64 IgA with sensitivity and specificity of 90%/90% and 95%/90%, respectively. The combined use of 3 or 4 antibodies further improved this performance to accuracies above 95%. After successful completion of anti-TB treatment at month 6, the levels of 16 kDa IgA and 16 kDa IgM dropped significantly whereas LAM IgG and TB-LTBI IgG increased. These results show the potential of extending investigation of anti-tuberculous IgG responses to include IgM and IgA responses against selected protein and non-protein antigens in differentiating active TB from other respiratory diseases in TB endemic settings.

A predictive signature gene set for discriminating active from latent tuberculosis in Warao Amerindian children.

PubMed

Verhagen, Lilly M; Zomer, Aldert; Maes, Mailis; Villalba, Julian A; Del Nogal, Berenice; Eleveld, Marc; van Hijum, Sacha Aft; de Waard, Jacobus H; Hermans, Peter Wm

2013-02-01

Tuberculosis (TB) continues to cause a high toll of disease and death among children worldwide. The diagnosis of childhood TB is challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. Whereas scientific and clinical research efforts to develop novel diagnostic tools have focused on TB in adults, childhood TB has been relatively neglected. Blood transcriptional profiling has improved our understanding of disease pathogenesis of adult TB and may offer future leads for diagnosis and treatment. No studies applying gene expression profiling of children with TB have been published so far. We identified a 116-gene signature set that showed an average prediction error of 11% for TB vs. latent TB infection (LTBI) and for TB vs. LTBI vs. healthy controls (HC) in our dataset. A minimal gene set of only 9 genes showed the same prediction error of 11% for TB vs. LTBI in our dataset. Furthermore, this minimal set showed a significant discriminatory value for TB vs. LTBI for all previously published adult studies using whole blood gene expression, with average prediction errors between 17% and 23%. In order to identify a robust representative gene set that would perform well in populations of different genetic backgrounds, we selected ten genes that were highly discriminative between TB, LTBI and HC in all literature datasets as well as in our dataset. Functional annotation of these genes highlights a possible role for genes involved in calcium signaling and calcium metabolism as biomarkers for active TB. These ten genes were validated by quantitative real-time polymerase chain reaction in an additional cohort of 54 Warao Amerindian children with LTBI, HC and non-TB pneumonia. Decision tree analysis indicated that five of the ten genes were sufficient to classify 78% of the TB cases correctly with no LTBI subjects wrongly classified as TB (100% specificity). Our data justify the further exploration of our signature set as biomarkers for potential childhood TB diagnosis. We show that, as the identification of different biomarkers in ethnically distinct cohorts is apparent, it is important to cross-validate newly identified markers in all available cohorts.

A predictive signature gene set for discriminating active from latent tuberculosis in Warao Amerindian children

PubMed Central

2013-01-01

Background Tuberculosis (TB) continues to cause a high toll of disease and death among children worldwide. The diagnosis of childhood TB is challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. Whereas scientific and clinical research efforts to develop novel diagnostic tools have focused on TB in adults, childhood TB has been relatively neglected. Blood transcriptional profiling has improved our understanding of disease pathogenesis of adult TB and may offer future leads for diagnosis and treatment. No studies applying gene expression profiling of children with TB have been published so far. Results We identified a 116-gene signature set that showed an average prediction error of 11% for TB vs. latent TB infection (LTBI) and for TB vs. LTBI vs. healthy controls (HC) in our dataset. A minimal gene set of only 9 genes showed the same prediction error of 11% for TB vs. LTBI in our dataset. Furthermore, this minimal set showed a significant discriminatory value for TB vs. LTBI for all previously published adult studies using whole blood gene expression, with average prediction errors between 17% and 23%. In order to identify a robust representative gene set that would perform well in populations of different genetic backgrounds, we selected ten genes that were highly discriminative between TB, LTBI and HC in all literature datasets as well as in our dataset. Functional annotation of these genes highlights a possible role for genes involved in calcium signaling and calcium metabolism as biomarkers for active TB. These ten genes were validated by quantitative real-time polymerase chain reaction in an additional cohort of 54 Warao Amerindian children with LTBI, HC and non-TB pneumonia. Decision tree analysis indicated that five of the ten genes were sufficient to classify 78% of the TB cases correctly with no LTBI subjects wrongly classified as TB (100% specificity). Conclusions Our data justify the further exploration of our signature set as biomarkers for potential childhood TB diagnosis. We show that, as the identification of different biomarkers in ethnically distinct cohorts is apparent, it is important to cross-validate newly identified markers in all available cohorts. PMID:23375113

Relationship between delayed embryonic development and metabolic factors and fat deposition in fruit bat Cynopterus sphinx.

PubMed

Banerjee, Arnab; Meenakumari, K J; Krishna, Amitabh

2007-01-01

The present study was undertaken in the fruit bat Cynopterus sphinx, which breeds twice in quick succession at Varanasi, India. Its gestation period varies significantly in the two successive pregnancies of the year owing to delayed embryonic development during the first (winter) pregnancy. The primary aim of the present study was to determine the role of metabolic factors in delayed embryonic development in the fruit bat C. sphinx. Variation in bodyweight, fat deposition, oxygen (O(2)) consumption rate, basal metabolic rate (BMR), body temperature (Tb) and hepatic succinate dehydrogenase (SDH) activity, along with circulating levels of thyroid hormones (tri-iodothyronine and thyroxine), were examined as metabolic factors during the two successive pregnancies in C. sphinx. The increase in bodyweight observed in November was due to accumulation of white adipose tissue in the posterior abdominal region. A significant decline in O(2) consumption rate, BMR, Tb and SDH activity was found in early winter in November-December, which coincides closely with the period of fat accumulation and with the period of delayed embryonic development in C. sphinx. A significantly higher O(2) consumption rate, BMR, Tb and SDH activity was noted during the second pregnancy in, when embryonic development was relatively faster. Thyroid hormone levels were high during the period of embryonic delay compared with levels during the remaining months. The results of the present study suggest that the delayed embryonic development in C. sphinx during early winter may be due to a low O(2) consumption rate, BMR, Tb and SDH activity in November-December. The energy saved by suppressing embryonic development in this species may be advantageous for fat accumulation. Increased thyroid hormone levels during the early winter period might facilitate fat accumulation in C. sphinx.

Characterization of 2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl Ureido Based Inhibitors of Trypanosoma brucei FolD and Testing for Antiparasitic Activity

PubMed Central

2015-01-01

The bifunctional enzyme N5,N10-methylenetetrahydrofolate dehydrogenase/cyclo hydrolase (FolD) is essential for growth in Trypanosomatidae. We sought to develop inhibitors of Trypanosoma brucei FolD (TbFolD) as potential antiparasitic agents. Compound 2 was synthesized, and the molecular structure was unequivocally assigned through X-ray crystallography of the intermediate compound 3. Compound 2 showed an IC50 of 2.2 μM, against TbFolD and displayed antiparasitic activity against T. brucei (IC50 49 μM). Using compound 2, we were able to obtain the first X-ray structure of TbFolD in the presence of NADP+ and the inhibitor, which then guided the rational design of a new series of potent TbFolD inhibitors. PMID:26322631

Detection of Mycobacterium tuberculosis peptides in the exosomes of patients with active and latent M. tuberculosis infection using MRM-MS.

PubMed

Kruh-Garcia, Nicole A; Wolfe, Lisa M; Chaisson, Lelia H; Worodria, William O; Nahid, Payam; Schorey, Jeff S; Davis, J Lucian; Dobos, Karen M

2014-01-01

The identification of easily measured, accurate diagnostic biomarkers for active tuberculosis (TB) will have a significant impact on global TB control efforts. Because of the host and pathogen complexities involved in TB pathogenesis, identifying a single biomarker that is adequately sensitive and specific continues to be a major hurdle. Our previous studies in models of TB demonstrated that exosomes, such as those released from infected macrophages, contain mycobacterial products, including many Mtb proteins. In this report, we describe the development of targeted proteomics assays employing multiplexed multiple reaction monitoring mass spectrometry (MRM-MS) in order to allow us to follow those proteins previously identified by western blot or shotgun mass spectrometry, and enhance biomarker discovery to include detection of Mtb proteins in human serum exosomes. Targeted MRM-MS assays were applied to exosomes isolated from human serum samples obtained from culture-confirmed active TB patients to detect 76 peptides representing 33 unique Mtb proteins. Our studies revealed the first identification of bacteria-derived biomarker candidates of active TB in exosomes from human serum. Twenty of the 33 proteins targeted for detection were found in the exosomes of TB patients, and included multiple peptides from 8 proteins (Antigen 85B, Antigen 85C, Apa, BfrB, GlcB, HspX, KatG, and Mpt64). Interestingly, all of these proteins are known mycobacterial adhesins and/or proteins that contribute to the intracellular survival of Mtb. These proteins will be included as target analytes in future validation studies as they may serve as markers for persistent active and latent Mtb infection. In summary, this work is the first step in identifying a unique and specific panel of Mtb peptide biomarkers encapsulated in exosomes and reveals complex biomarker patterns across a spectrum of TB disease states.

Detection of Mycobacterium tuberculosis Peptides in the Exosomes of Patients with Active and Latent M. tuberculosis Infection Using MRM-MS

PubMed Central

Kruh-Garcia, Nicole A.; Wolfe, Lisa M.; Chaisson, Lelia H.; Worodria, William O.; Nahid, Payam; Schorey, Jeff S.; Davis, J. Lucian; Dobos, Karen M.

2014-01-01

The identification of easily measured, accurate diagnostic biomarkers for active tuberculosis (TB) will have a significant impact on global TB control efforts. Because of the host and pathogen complexities involved in TB pathogenesis, identifying a single biomarker that is adequately sensitive and specific continues to be a major hurdle. Our previous studies in models of TB demonstrated that exosomes, such as those released from infected macrophages, contain mycobacterial products, including many Mtb proteins. In this report, we describe the development of targeted proteomics assays employing multiplexed multiple reaction monitoring mass spectrometry (MRM-MS) in order to allow us to follow those proteins previously identified by western blot or shotgun mass spectrometry, and enhance biomarker discovery to include detection of Mtb proteins in human serum exosomes. Targeted MRM-MS assays were applied to exosomes isolated from human serum samples obtained from culture-confirmed active TB patients to detect 76 peptides representing 33 unique Mtb proteins. Our studies revealed the first identification of bacteria-derived biomarker candidates of active TB in exosomes from human serum. Twenty of the 33 proteins targeted for detection were found in the exosomes of TB patients, and included multiple peptides from 8 proteins (Antigen 85B, Antigen 85C, Apa, BfrB, GlcB, HspX, KatG, and Mpt64). Interestingly, all of these proteins are known mycobacterial adhesins and/or proteins that contribute to the intracellular survival of Mtb. These proteins will be included as target analytes in future validation studies as they may serve as markers for persistent active and latent Mtb infection. In summary, this work is the first step in identifying a unique and specific panel of Mtb peptide biomarkers encapsulated in exosomes and reveals complex biomarker patterns across a spectrum of TB disease states. PMID:25080351

Association between traditional systemic antipsoriatic drugs and tuberculosis risk in patients with psoriasis with or without psoriatic arthritis: results of a nationwide cohort study from Taiwan.

PubMed

Chen, Yi-Ju; Wu, Chun-Ying; Shen, Jui-Lung; Chen, Tzu-Ting; Chang, Yun-Ting

2013-07-01

Although the link between tuberculosis (TB) and biologics use is well established, the risk of TB among patients with psoriasis exposed to traditional systemic therapies remains elusive. The aim is to investigate the association between traditional systemic therapies and TB among patients with psoriasis. We conducted a retrospective cohort study on the risk of active TB among patients with psoriasis and psoriatic arthritis, using the National Health Insurance Research Database of Taiwan, 1996 through 2008. Standardized incidence ratios of TB were analyzed in comparison with age- and gender-matched general population. Logistic regression was used in a nested case-control analysis to estimate the odds ratios of TB related to exposure to traditional systemic agents during the year before TB development. Among the 81,266 patients in the psoriasis cohort, 497 new active TB cases were identified. The incidence rate of TB was 102 cases per 100,000 person-years among patients with psoriasis (standardized incidence ratio 1.22, 95% confidence interval 1.18-1.33). The risk of TB was higher in patients with severe disease (standardized incidence ratio 1.52, 95% confidence interval 1.46-1.74). To facilitate comparisons with the 497 active TB cases, a total of 1988 matched control subjects were selected for a nested case-control study. Patients taking systemic corticosteroids and nonsteroidal anti-inflammatory drugs were associated with higher incidence of TB, especially frequent users, after adjustment for multiple TB risk factors, drug exposures, hospital visits, and level of urbanization. Stratified analyses of current users and new users of these drugs revealed similar results. Finally, traditional systemic antipsoriatic treatment was not associated with TB on any of the analyses. The National Health Insurance Research Database did not contain information regarding severity of psoriasis, smoking status, alcohol use, diet, laboratory parameters, chest radiograph, or history of recent contact with an individual with TB. Misclassification of disease cannot be ruled out in a registry-based database. The accessibility of health care may be associated with the level of urbanization, which could confound the effect of drugs in multivariate analyses. Severe psoriasis may be associated with an elevated TB risk. Traditional systemic therapies do not seem to be strongly associated with TB occurrence. Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Targeted screening and treatment for latent tuberculosis infection using QuantiFERON-TB Gold is cost-effective in Mexico.

PubMed

Burgos, J L; Kahn, J G; Strathdee, S A; Valencia-Mendoza, A; Bautista-Arredondo, S; Laniado-Laborin, R; Castañeda, R; Deiss, R; Garfein, R S

2009-08-01

To assess the cost-effectiveness of screening for latent tuberculosis infection (LTBI) using a commercially available detection test and treating individuals at high risk for human immunodeficiency virus (HIV) infection in a middle-income country. We developed a Markov model to evaluate the cost per LTBI case detected, TB case averted and quality-adjusted life year (QALY) gained for a cohort of 1000 individuals at high risk for HIV infection over 20 years. Baseline model inputs for LTBI prevalence were obtained from published literature and cross-sectional data from tuberculosis (TB) screening using QuantiFERON-TB Gold In-Tube (QFT-GIT) testing among sex workers and illicit drug users at high risk for HIV recruited through street outreach in Tijuana, Mexico. Costs are reported in 2007 US dollars. Future costs and QALYs were discounted at 3% per year. Sensitivity analyses were performed to evaluate model robustness. Over 20 years, we estimate the program would prevent 78 cases of active TB and 55 TB-related deaths. The incremental cost per case of LTBI detected was US$730, cost per active TB averted was US$529 and cost per QALY gained was US$108. In settings of endemic TB and escalating HIV incidence, targeting LTBI screening and treatment among high-risk groups may be highly cost-effective.

Predicting tuberculosis risk in the foreign-born population of British Columbia, Canada: study protocol for a retrospective population-based cohort study

PubMed Central

Ronald, Lisa A; Campbell, Jonathon R; Balshaw, Robert F; Roth, David Z; Romanowski, Kamila; Marra, Fawziah; Cook, Victoria J; Johnston, James C

2016-01-01

Introduction Improved understanding of risk factors for developing active tuberculosis (TB) will better inform decisions about diagnostic testing and treatment for latent TB infection (LTBI) in migrant populations in low-incidence regions. We aim to examine TB risk factors among the foreign-born population in British Columbia (BC), Canada, and to create and validate a clinically relevant multivariate risk score to predict active TB. Methods and analysis This retrospective population-based cohort study will include all foreign-born individuals who acquired permanent resident status in Canada between 1 January 1985 and 31 December 2013 and acquired healthcare coverage in BC at any point during this period. Multiple administrative databases and disease registries will be linked, including a National Immigration Database, BC Provincial Health Insurance Registration, physician billings, hospitalisations, drugs dispensed from community pharmacies, vital statistics, HIV testing and notifications, cancer, chronic kidney disease and dialysis treatment, and all TB and LTBI testing and treatment data in BC. Extended proportional hazards regression will be used to estimate risk factors for TB and to create a prognostic TB risk score. Ethics and dissemination Ethical approval for this study has been obtained from the University of British Columbia Clinical Ethics Review Board. Once completed, study findings will be presented at conferences and published in peer-reviewed journals. An online TB risk score calculator will also be created. PMID:27888179

Targeted screening and treatment for latent tuberculosis infection using QuantiFERON®-TB Gold is cost-effective in Mexico

PubMed Central

Burgos, J. L.; Kahn, J. G.; Strathdee, S. A.; Valencia-Mendoza, A.; Bautista-Arredondo, S.; Laniado-Laborin, R.; Castañeda, R.; Deiss, R.; Garfein, R. S.

2009-01-01

SUMMARY OBJECTIVE To assess the cost-effectiveness of screening for latent tuberculosis infection (LTBI) using a commercially available detection test and treating individuals at high risk for human immunodeficiency virus (HIV) infection in a middle-income country. DESIGN We developed a Markov model to evaluate the cost per LTBI case detected, TB case averted and quality-adjusted life year (QALY) gained for a cohort of 1000 individuals at high risk for HIV infection over 20 years. Baseline model inputs for LTBI prevalence were obtained from published literature and cross-sectional data from tuberculosis (TB) screening using QuantiFERON®-TB Gold In-Tube (QFT-GIT) testing among sex workers and illicit drug users at high risk for HIV recruited through street outreach in Tijuana, Mexico. Costs are reported in 2007 US dollars. Future costs and QALYs were discounted at 3% per year. Sensitivity analyses were performed to evaluate model robustness. RESULTS Over 20 years, we estimate the program would prevent 78 cases of active TB and 55 TB-related deaths. The incremental cost per case of LTBI detected was US$730, cost per active TB averted was US$529 and cost per QALY gained was US$108. CONCLUSIONS In settings of endemic TB and escalating HIV incidence, targeting LTBI screening and treatment among high-risk groups may be highly cost-effective. PMID:19723375

Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development.

PubMed

Tanner, Lloyd; Denti, Paolo; Wiesner, Lubbe; Warner, Digby F

2018-06-22

Anti-tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective "lesion-penetrating" properties of the front-line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment-shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti-TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism. However, while there is a fundamental requirement to understand the mode of action and pharmacological properties of any current or experimental anti-TB agent within the context of the obligate human host, this is complex and, until recently, has been severely limited by the available methodologies and models. Here, we discuss advances in analytical models and technologies which have enabled investigations of drug metabolism and pharmacokinetics (DMPK) for new TB drug development. In particular, we consider the potential to shift the focus of traditional pharmacokinetic-pharmacodynamic analyses away from plasma to a more specific "site of action" drug exposure as an essential criterion for drug development and the design of dosing strategies. Moreover, in summarising approaches to determine DMPK data for the "unit of infection" comprising host macrophage and intracellular bacillus, we evaluate the potential benefits of including these analyses at an early stage in the preclinical drug development algorithm. © 2018 IUBMB Life, 2018. © 2018 International Union of Biochemistry and Molecular Biology.

Joint effect of MCP-1 genotype GG and MMP-1 genotype 2G/2G increases the likelihood of developing pulmonary tuberculosis in BCG-vaccinated individuals.

PubMed

Ganachari, Malathesha; Ruiz-Morales, Jorge A; Gomez de la Torre Pretell, Juan C; Dinh, Jeffrey; Granados, Julio; Flores-Villanueva, Pedro O

2010-01-25

We previously reported that the -2518 MCP-1 genotype GG increases the likelihood of developing tuberculosis (TB) in non-BCG-vaccinated Mexicans and Koreans. Here, we tested the hypothesis that this genotype, alone or together with the -1607 MMP-1 functional polymorphism, increases the likelihood of developing TB in BCG-vaccinated individuals. We conducted population-based case-control studies of BCG-vaccinated individuals in Mexico and Peru that included 193 TB cases and 243 healthy tuberculin-positive controls from Mexico and 701 TB cases and 796 controls from Peru. We also performed immunohistochemistry (IHC) analysis of lymph nodes from carriers of relevant two-locus genotypes and in vitro studies to determine how these variants may operate to increase the risk of developing active disease. We report that a joint effect between the -2518 MCP-1 genotype GG and the -1607 MMP-1 genotype 2G/2G consistently increases the odds of developing TB 3.59-fold in Mexicans and 3.9-fold in Peruvians. IHC analysis of lymph nodes indicated that carriers of the two-locus genotype MCP-1 GG MMP-1 2G/2G express the highest levels of both MCP-1 and MMP-1. Carriers of these susceptibility genotypes might be at increased risk of developing TB because they produce high levels of MCP-1, which enhances the induction of MMP-1 production by M. tuberculosis-sonicate antigens to higher levels than in carriers of the other two-locus MCP-1 MMP-1 genotypes studied. This notion was supported by in vitro experiments and luciferase based promoter activity assay. MMP-1 may destabilize granuloma formation and promote tissue damage and disease progression early in the infection. Our findings may foster the development of new and personalized therapeutic approaches targeting MCP-1 and/or MMP-1.

Joint Effect of MCP-1 Genotype GG and MMP-1 Genotype 2G/2G Increases the Likelihood of Developing Pulmonary Tuberculosis in BCG-Vaccinated Individuals

PubMed Central

Ganachari, Malathesha; Ruiz-Morales, Jorge A.; Gomez de la Torre Pretell, Juan C.; Dinh, Jeffrey; Granados, Julio; Flores-Villanueva, Pedro O.

2010-01-01

We previously reported that the – 2518 MCP-1 genotype GG increases the likelihood of developing tuberculosis (TB) in non-BCG-vaccinated Mexicans and Koreans. Here, we tested the hypothesis that this genotype, alone or together with the – 1607 MMP-1 functional polymorphism, increases the likelihood of developing TB in BCG-vaccinated individuals. We conducted population-based case-control studies of BCG-vaccinated individuals in Mexico and Peru that included 193 TB cases and 243 healthy tuberculin-positive controls from Mexico and 701 TB cases and 796 controls from Peru. We also performed immunohistochemistry (IHC) analysis of lymph nodes from carriers of relevant two-locus genotypes and in vitro studies to determine how these variants may operate to increase the risk of developing active disease. We report that a joint effect between the – 2518 MCP-1 genotype GG and the – 1607 MMP-1 genotype 2G/2G consistently increases the odds of developing TB 3.59-fold in Mexicans and 3.9-fold in Peruvians. IHC analysis of lymph nodes indicated that carriers of the two-locus genotype MCP-1 GG MMP-1 2G/2G express the highest levels of both MCP-1 and MMP-1. Carriers of these susceptibility genotypes might be at increased risk of developing TB because they produce high levels of MCP-1, which enhances the induction of MMP-1 production by M. tuberculosis-sonicate antigens to higher levels than in carriers of the other two-locus MCP-1 MMP-1 genotypes studied. This notion was supported by in vitro experiments and luciferase based promoter activity assay. MMP-1 may destabilize granuloma formation and promote tissue damage and disease progression early in the infection. Our findings may foster the development of new and personalized therapeutic approaches targeting MCP-1 and/or MMP-1. PMID:20111728

Influence of diabetes mellitus on immunity to human tuberculosis.

PubMed

Kumar Nathella, Pavan; Babu, Subash

2017-09-01

Type 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co-morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease. © 2017 John Wiley & Sons Ltd.

Prevalence of Pulmonary Tuberculosis among Prison Inmates in Ethiopia, a Cross-Sectional Study

PubMed Central

Ali, Solomon; Haileamlak, Abraham; Wieser, Andreas; Pritsch, Michael; Heinrich, Norbert; Loscher, Thomas; Hoelscher, Michael; Rachow, Andrea

2015-01-01

Setting Tuberculosis (TB) is one of the major health problems in prisons. Objective This study was done to assess the prevalence and determinants of active tuberculosis in Ethiopian prisons. Design A cross-sectional study was conducted from January 2013 to December 2013 in 13 zonal prisons. All incarcerated inmates underwent TB symptom screening according to WHO criteria. From identified TB-suspects two sputum samples were analyzed using smear microscopy and solid culture. A standardized questionnaire assessing TB risk factors was completed for each TB suspect. Results 765 (4.9%) TB suspects were identified among 15,495 inmates. 51 suspects were already on anti-TB treatment (6.67%) and 20 (2.8%) new culture-confirmed TB cases were identified in the study, resulting in an overall TB prevalence of 458.1/100,000 (95%CI: 350-560/100,000). Risk factors for active TB were alcohol consumption, contact with a TB case before incarceration and no window in prison cell. HIV prevalence was not different between TB suspects and active TB cases. Further, the TB burden in prisons increased with advancing distance from the capital Addis Ababa. Conclusions The overall TB prevalence in Ethiopian prisons was high and extremely variable among different prisons. TB risk factors related to conditions of prison facilities and the impact of implemented TB control measures need to be further studied in order to improve TB control among inmates. PMID:26641654

Persistent Latent Tuberculosis Reactivation Risk in United States Immigrants

PubMed Central

Painter, John; Parker, Matthew; Lowenthal, Phillip; Flood, Jennifer; Fu, Yunxin; Asis, Redentor; Reves, Randall

2014-01-01

Rationale: Current guidelines limit latent tuberculosis infection (LTBI) evaluation to persons in the United States less than or equal to 5 years based on the assumption that high TB rates among recent entrants are attributable to high LTBI reactivation risk, which declines over time. We hypothesized that high postarrival TB rates may instead be caused by imported active TB. Objectives: Estimate reactivation and imported TB in an immigrant cohort. Methods: We linked preimmigration records from a cohort of California-bound Filipino immigrants during 2001–2010 with subsequent TB reports. TB was likely LTBI reactivation if the immigrant had no evidence of active TB at preimmigration examination, likely imported if preimmigration radiograph was abnormal and TB was reported less than or equal to 6 months after arrival, and likely reactivation of inactive TB if radiograph was abnormal but TB was reported more than 6 months after arrival. Measurements and Main Results: Among 123,114 immigrants, 793 TB cases were reported. Within 1 year of preimmigration examination, 85% of TB was imported; 6 and 9% were reactivation of LTBI and inactive TB, respectively. Conversely, during Years 2–9 after U.S. entry, 76 and 24% were reactivation of LTBI and inactive TB, respectively. The rate of LTBI reactivation (32 per 100,000) did not decline during Years 1–9. Conclusions: High postarrival TB rates were caused by detection of imported TB through active postarrival surveillance. Among immigrants without active TB at baseline, reported TB did not decline over 9 years, indicating sustained high risk of LTBI reactivation. Revised guidelines should support LTBI screening and treatment more than 5 years after U.S. arrival. PMID:24308495

New target prediction and visualization tools incorporating open source molecular fingerprints for TB Mobile 2.0

PubMed Central

2014-01-01

Background We recently developed a freely available mobile app (TB Mobile) for both iOS and Android platforms that displays Mycobacterium tuberculosis (Mtb) active molecule structures and their targets with links to associated data. The app was developed to make target information available to as large an audience as possible. Results We now report a major update of the iOS version of the app. This includes enhancements that use an implementation of ECFP_6 fingerprints that we have made open source. Using these fingerprints, the user can propose compounds with possible anti-TB activity, and view the compounds within a cluster landscape. Proposed compounds can also be compared to existing target data, using a näive Bayesian scoring system to rank probable targets. We have curated an additional 60 new compounds and their targets for Mtb and added these to the original set of 745 compounds. We have also curated 20 further compounds (many without targets in TB Mobile) to evaluate this version of the app with 805 compounds and associated targets. Conclusions TB Mobile can now manage a small collection of compounds that can be imported from external sources, or exported by various means such as email or app-to-app inter-process communication. This means that TB Mobile can be used as a node within a growing ecosystem of mobile apps for cheminformatics. It can also cluster compounds and use internal algorithms to help identify potential targets based on molecular similarity. TB Mobile represents a valuable dataset, data-visualization aid and target prediction tool. PMID:25302078

New target prediction and visualization tools incorporating open source molecular fingerprints for TB Mobile 2.0.

PubMed

Clark, Alex M; Sarker, Malabika; Ekins, Sean

2014-01-01

We recently developed a freely available mobile app (TB Mobile) for both iOS and Android platforms that displays Mycobacterium tuberculosis (Mtb) active molecule structures and their targets with links to associated data. The app was developed to make target information available to as large an audience as possible. We now report a major update of the iOS version of the app. This includes enhancements that use an implementation of ECFP_6 fingerprints that we have made open source. Using these fingerprints, the user can propose compounds with possible anti-TB activity, and view the compounds within a cluster landscape. Proposed compounds can also be compared to existing target data, using a näive Bayesian scoring system to rank probable targets. We have curated an additional 60 new compounds and their targets for Mtb and added these to the original set of 745 compounds. We have also curated 20 further compounds (many without targets in TB Mobile) to evaluate this version of the app with 805 compounds and associated targets. TB Mobile can now manage a small collection of compounds that can be imported from external sources, or exported by various means such as email or app-to-app inter-process communication. This means that TB Mobile can be used as a node within a growing ecosystem of mobile apps for cheminformatics. It can also cluster compounds and use internal algorithms to help identify potential targets based on molecular similarity. TB Mobile represents a valuable dataset, data-visualization aid and target prediction tool.

Increased mortality associated with treated active tuberculosis in HIV-infected adults in Tanzania

PubMed Central

Kabali, Conrad; Mtei, Lillian; Brooks, Daniel R.; Waddell, Richard; Bakari, Muhammad; Matee, Mecky; Arbeit, Robert D.; Pallangyo, Kisali; von Reyn, C. Fordham; Horsburgh, C. Robert

2013-01-01

SUMMARY Active tuberculosis (TB) among HIV-infected patients, even when successfully treated, may be associated with excess mortality. We conducted a prospective cohort study nested in a randomized TB vaccine trial to compare mortality between HIV-infected patients diagnosed and treated for TB (TB, n=77) and HIV-infected patients within the same CD4 range, who were not diagnosed with or treated for active TB (non-TB, n=308) in the period 2001–2008. Only twenty four subjects (6%) were on antiretroviral therapy at the beginning of this study. After accounting for covariate effects including use of antiretroviral therapy, isoniazid preventive therapy, and receipt of vaccine, we found a four-fold increase in mortality in TB patients compared with non-TB patients (adjusted Hazard Ratio 4.61; 95% Confidence Interval (CI): 1.63, 13.05). These findings suggest that treatment for TB alone is not sufficient to avert the excess mortality associated with HIV-related TB and that prevention of TB may provide a mortality benefit. PMID:23523641

Interdisciplinary Public Health Intervention in a Multigenerational Tuberculosis (TB) Outbreak in Harris County, Texas: A Case Study with Implications for Disease Control Process Improvement and Transmission Cycle Interruption

PubMed Central

Haynie, Aisha; Plasencia, Carlos; Fields, Kimberly; Nesbitt, Elna; Lovings-Clark, Audrey; Scott, Mary; Wiltz-Beckham, Dana; Reed, Brian; Shah, Umair A

2017-01-01

Abstract Background Harris County Public Health (HCPH) is the health department for Harris County, Texas jurisdiction. Harris County as a whole is the nation’s third most populous county, with 4.3 million residents, and a TB case rate more than double that of the USA. (7.6 cases per 100,000 pop). A total, 327 individuals were diagnosed with TB in Harris County during 2015, over two-thirds occurring in foreign-born individuals. In 2016, HCPH treated an immigrant female with active TB. Initial contact investigation (CI) yielded five household contacts (HHC). Two tested positive, but refused subsequent clinical evaluation by HCPH. Two months later, HCPH was notified of a HHC hospitalized with TB. After hospital discharge, the sick HHC moved into a motel in attempts to self-isolate, but refused evaluation of additional HHC in the home, and banned home access, precluding adequate CI. After numerous phone calls, visits to motel and home, and multiple rescheduled appointments, legal action appeared inevitable. Days later, HCPH was notified of another HHC diagnosed with active TB. Methods With alarm regarding the family’s adherence to control orders, TB staff implemented an innovative multidisciplinary team-based intervention in hopes of avoiding legal action. A site visit was paid to the motel by a local health authority, two TB staff, a county public investigator, and a refugee clinic outreach worker fluent in the family’s language. Patients were presented with letters requesting immediate cooperation to avoid court filings. Questions were answered, misinformation corrected, and education provided. Results Intermediary on-site intervention using a compassionate, firm multidisciplinary team approach resulted in 16 additional family members tested, yielding an infant with active TB (Case 4) and 8 with TB Infection (TBI). Isolation breaches were also discovered. Most importantly, TB transmission cycle was interrupted. Cultural and economic barriers hindering successful interaction with family were addressed, TB misconceptions corrected, and trusting relationship developed. Conclusion This innovative multidisciplinary intervention avoided court proceedings and curtailed the TB transmission cycle. HCPH improved its non-adherence intervention process, and modified TB control orders for infectious patients residing in congregate settings. Disclosures All authors: No reported disclosures.

Interleukin-1 receptor antagonist, a biomarker of response to anti-TB treatment in HIV/TB co-infected patients.

PubMed

Nouhin, Janin; Pean, Polidy; Madec, Yoann; Chevalier, Mathieu F; Didier, Celine; Borand, Laurence; Blanc, François-Xavier; Scott-Algara, Daniel; Laureillard, Didier; Weiss, Laurence

2017-05-01

Despite the high frequency of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in human immunodeficiency virus (HIV)/TB co-infected patients, no diagnostic test is available. Here, we investigated whether monocyte/macrophage activation markers can predict TB-IRIS occurrence and if they are modulated by anti-TB treatment. Frozen plasma was obtained from 127 HIV/TB co-infected adults naïve for antiretroviral therapy, enrolled in the CAMELIA trial, 36 of whom developed TB-IRIS. Concentrations of IL-1Ra, sCD14, and sCD163 were measured at anti-TB treatment onset (baseline), after 8 weeks of anti-TB treatment and at TB-IRIS time. At baseline, IL-1Ra and sCD14 concentrations were similar in TB-IRIS and non-IRIS patients. sCD163 concentrations, although significantly higher in TB-IRIS patients, did not remain associated with TB-IRIS occurrence in multivariate analysis. At the time of TB-IRIS, patients displayed higher concentrations of IL-1Ra (p = 0.002) and sCD14 (p < 0.001). The most striking result was the significant decrease in IL-1Ra after 8 weeks of anti-TB treatment (median reduction: -63% (p < 0.0001)). None of the biomarkers tested was associated with TB-IRIS occurrence. However, repeated measurement of IL-1Ra could help for the diagnosis of TB-IRIS. The substantial reduction of IL-1Ra under treatment suggests that IL-1Ra could be a surrogate biomarker of anti-TB treatment response in HIV-infected patients. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Tuberculosis-a World Health Organization Perspective.

PubMed

Sotgiu, Giovanni; Sulis, Giorgia; Matteelli, Alberto

2017-01-01

Tuberculosis (TB) is an important cause of morbidity and mortality worldwide. The World Health Organization (WHO) has implemented and scaled-up three important global public health strategies (i.e., DOTS, Stop TB, and End TB) to improve the international scenario. Their epidemiological impact was relevant, as they decreased the number of potential new cases of disease and death. However, the emergence and spread of TB/HIV coinfection and multidrug-resistant TB have hindered the progress towards the elimination of TB by 2050. More efforts are required to increase the global annual decline of the TB incidence rate. Political commitment is necessary, with global and national strategies oriented to the adoption and adaptation of the international, evidence-based recommendations on diagnosis, treatment, and prevention. Research and development activities should be planned to improve the current tools adopted to fight the disease. New rapid diagnostics, an updated and effective therapeutic armamentarium, and an effective preventive vaccine could represent the solution to address the current epidemiological threats.

Isolation, purification, and immunological activities of a low-molecular-weight polysaccharide from the Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (higher Basidiomycetes).

PubMed

Zhu, Lina; Luo, Xi; Tang, Qingjiu; Liu, Yanfang; Zhou, Shuai; Yang, Yan; Zhang, Jingsong

2013-01-01

To obtain a low-molecular-weight polysaccharide with immuno-enhancing activity, hot water extract of Ganoderma lucidum fruit bodies was separated by membrane ultrafiltration, anion exchange, and gel filtration chromatography, and the immunological activities of fractions were assessed on the basis of nitric oxide production by RAW 264.7 macrophages. A novel polysaccharide (TB3-2-2) was successfully isolated and purified. TB3-2-2 is a homogeneous polysaccharide, with a relative molecular weight of 5.11 × 103 Da, identified by high-performance liquid chromatography and was composed of galactose and glucose in a molar ratio of 2:3 determined by high-performance anion exchange chromatography. TB3-2-2 had a carbohydrate content of 99%, as measured using the phenol-sulfuric acid method. Proliferation of mouse spleen lymphocytes and the expression level of interleukin-6 was significantly increased by TB3-2-2. Results indicate that the low-molecular-weight polysaccharide with immunological activity in G. lucidum is worthy of further research and development.

European Union Standards for Tuberculosis Care

PubMed Central

Migliori, G.B.; Zellweger, J.P.; Abubakar, I.; Ibraim, E.; Caminero, J.A.; De Vries, G.; D'Ambrosio, L.; Centis, R.; Sotgiu, G.; Menegale, O.; Kliiman, K.; Aksamit, T.; Cirillo, D.M.; Danilovits, M.; Dara, M.; Dheda, K.; Dinh-Xuan, A.T.; Kluge, H.; Lange, C.; Leimane, V.; Loddenkemper, R.; Nicod, L.P.; Raviglione, M.C.; Spanevello, A.; Thomsen, V.Ø.; Villar, M.; Wanlin, M.; Wedzicha, J.A.; Zumla, A.; Blasi, F.; Huitric, E.; Sandgren, A.; Manissero, D.

2012-01-01

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination. PMID:22467723

Screening contacts of patients with extrapulmonary TB for latent TB infection.

PubMed

Humphreys, Anna; Abbara, Aula; Williams, Sion; John, Laurence; Corrah, Tumena; McGregor, Alastair; Davidson, Robert N

2018-03-01

2016 TB National Institute for Health and Care Excellence (NICE) guidelines imply that contacts of extrapulmonary TB do not require screening for latent TB infection. At our high TB prevalence site, we identified 189 active cases of TB for whom there were 698 close contacts. 29.1% of the contacts of pulmonary TB and 10.7% of the contacts of extrapulmonary TB had active or latent TB infection. This supports screening contacts of extrapulmonary TB at our site and presents a way to access high-risk individuals. We propose to continue to screen the contacts of our patients with extrapulmonary TB and recommend other TB units audit their local results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Tuberculosis Comorbidity with Communicable and Noncommunicable Diseases

PubMed Central

Bates, Matthew; Marais, Ben J.; Zumla, Alimuddin

2015-01-01

The 18th WHO Global Tuberculosis Annual Report indicates that there were an estimated 8.6 million incident cases of tuberculosis (TB) in 2012, which included 2.9 million women and 530,000 children. TB caused 1.3 million deaths including 320,000 human immunodeficiency virus (HIV)-infected people; three-quarters of deaths occurred in Africa and Southeast Asia. With one-third of the world’s population latently infected with Mycobacterium tuberculosis (Mtb), active TB disease is primarily associated with a break down in immune surveillance. This explains the strong link between active TB disease and other communicable diseases (CDs) or noncommunicable diseases (NCDs) that exert a toll on the immune system. Comorbid NCD risk factors include diabetes, smoking, malnutrition, and chronic lung disease, all of which have increased relentlessly over the past decade in developing countries. The huge overlap between killer infections such as TB, HIV, malaria, and severe viral infections with NCDs, results in a “double burden of disease” in developing countries. The current focus on vertical disease programs fails to recognize comorbidities or to encourage joint management approaches. This review highlights major disease overlaps and discusses the rationale for better integration of tuberculosis care with services for NCDs and other infectious diseases to enhance the overall efficiency of the public health responses. PMID:25659380

A survey of tuberculosis infection control practices at the NIH/NIAID/DAIDS-supported clinical trial sites in low and middle income countries.

PubMed

Godfrey, Catherine; Tauscher, Gail; Hunsberger, Sally; Austin, Melissa; Scott, Lesley; Schouten, Jeffrey T; Luetkemeyer, Anne F; Benson, Constance; Coombs, Robert; Swindells, Susan

2016-06-10

Health care associated transmission of Mycobacterium tuberculosis (TB) is well described. A previous survey of infection control (IC) practices at clinical research sites in low and middle income countries (LMIC) funded by the National Institute of Allergy and Infectious Diseases (NIAID) conducting HIV research identified issues with respiratory IC practices. A guideline for TB IC based on international recommendations was developed and promulgated. This paper reports on adherence to the guideline at sites conducting or planning to conduct TB studies with the intention of supporting improvement. A survey was developed that assessed IC activities in three domains: facility level measures, administrative control measures and environmental measures. An external site monitor visited each site in 2013-2014, to complete the audit. A central review committee evaluated the site-level survey and results were tabulated. Fisher's exact test was performed to determine whether there were significant differences in practices at sites that had IC officers versus sites that did not have IC officers. Significance was assessed at p

Dietary Intake of Antioxidant Vitamins and Carotenoids and Risk of Developing Active Tuberculosis in a Prospective Population-Based Cohort Study.

PubMed

Soh, Avril Z; Chee, Cynthia B E; Wang, Yee-Tang; Yuan, Jian-Min; Koh, Woon-Puay

2017-08-15

Antioxidants may protect against oxidative stress, which is associated with tuberculosis (TB) disease. However, direct evidence for a protective association between dietary antioxidants and TB incidence in humans has been lacking. The relationship between intake of antioxidant vitamins (vitamins A, C, D, and E) and individual carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein) and TB incidence was examined in the Singapore Chinese Health Study, a prospective cohort study of 63,257 adults aged 45-74 years enrolled during 1993-1998. Baseline intake of these antioxidants was estimated using a validated semiquantitative food frequency questionnaire including questions on use of dietary supplements. After an average of 16.9 years of follow-up, 1,186 incident active TB cases were identified among cohort participants. Compared with the lowest quartile, reduced risk of active TB was observed for the highest quartile of vitamin A intake (hazard ratio = 0.71, 95% confidence interval: 0.59, 0.85; P-trend < 0.01) and β-carotene intake (hazard ratio = 0.76, 95% confidence interval: 0.63, 0.91; P-trend < 0.01), regardless of smoking status. Lower TB risk was seen for vitamin C intake among current smokers only. Other vitamins and carotenoids were not associated with TB risk. These results suggest that vitamin C may reduce TB risk among current smokers by ameliorating oxidative stress, while vitamin A and β-carotene may have additional antimycobacterial properties. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

[Biologics and mycobacterial diseases].

PubMed

Tsuyuguchi, Kazunari; Matsumoto, Tomoshige

2013-03-01

Various biologics such as TNF-alpha inhibitor or IL-6 inhibitor are now widely used for treatment of rheumatoid arthritis. Many reports suggested that one of the major issues is high risk of developing tuberculosis (TB) associated with using these agents, which is especially important in Japan where tuberculosis still remains endemic. Another concern is the risk of development of nontuberculous mycobacterial (NTM) diseases and we have only scanty information about it. The purpose of this symposium is to elucidate the role of biologics in the development of mycobacterial diseases and to establish the strategy to control them. First, Dr. Tohma showed the epidemiologic data of TB risks associated with using biologics calculated from the clinical database on National Database of Rheumatic Diseases by iR-net in Japan. He estimated TB risks in rheumatoid arthritis (RA) patients to be about four times higher compared with general populations and to become even higher by using biologics. He also pointed out a low rate of implementation of QuantiFERON test (QFT) as screening test for TB infection. Next, Dr. Tokuda discussed the issue of NTM disease associated with using biologics. He suggested the airway disease in RA patients might play some role in the development of NTM disease, which may conversely lead to overdiagnosis of NTM disease in RA patients. He suggested that NTM disease should not be uniformly considered a contraindication to treatment with biologics, considering from the results of recent multicenter study showing relatively favorable outcome of NTM patients receiving biologics. Patients with latent tuberculosis infection (LTBI) should receive LTBI treatment before starting biologics. Dr. Kato, a chairperson of the Prevention Committee of the Japanese Society for Tuberculosis, proposed a new LTBI guideline including active implementation of LTBI treatment, introducing interferon gamma release assay, and appropriate selection of persons at high risk for developing TB. Lastly, Dr. Matsumoto stressed the risk of discontinuing TNF-alpha inhibitor during treatment for tuberculosis. He showed from his clinical experience that TNF-alpha inhibitor can be safely used in active TB patient receiving effective antituberculosis chemotherapy and it is even more effective for prevention of paradoxical response. Active discussion was done about the four topics, including the matter beyond present guidelines. We hope these discussions will form the basis for the establishment of new guideline for the management of mycobacterial disease when using immunosuppressive agents including biologics. 1. The risk of developing tuberculosis (TB) and situations of screening for TB risk at administration of biologics-the case of rheumatoid arthritis: Shigeto TOHMA (Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital) We calculated the standardized incidence ratio (SIR) of TB from the clinical data on National Database of Rheumatic Diseases by iR-net in Japan (NinJa) and compared with the SIR of TB from the data of the post-marketing surveillances of five biologics. Among 43584 patient-years, forty patients developed TB. The SIR of TB in NinJa was 4.34 (95%CI: 3.00-5.69). According to the post-marketing surveillances of 5 biologics, the SIR of TB were 3.62-34.4. The incidence of TB in patients with RA was higher than general population in Japan, and was increased more by some biologics. We have to recognize the risk of TB when we start biologics therapy to patients with RA. Although the frequency of implementation of QuantiFERON test (QFT) had gradually increased, it was still limited to 41%. In order to predict the risk of developing TB and to prevent TB, it might be better to check all RA patients by QFT at time time of biologics administration. 2. Biologics and nontuberculous mycobacterial diseases: Hitoshi TOKUDA (Social Insurance Central General Hospital) Several topics about the relationship between RA and nontuberculous mycobacterial (NTM) diseases were discussed, which is still poorly understood. It is well known that airway diseases often accompany RA, which may be considered as a possible etiology for development of NTM diseases, but conversely it may lead to overdiagnosis of NTM disease. Next, we evaluated justification for the contraindication of biologics in patients with NTM diseases. Recent multicenter study showed that prognosis of patients developing NTM diseases during treatment with biologics were not always poor, which throws doubt on uniform prohibition of biologics in NTM diseases. 3. Future guideline for treating latent tuberculosis infection: Seiya KATO (Research Institute of Tuberculosis, Japan AntiTuberculosis Association) The Japanese Society for Tuberculosis issued a joint statement on chemoprophylaxis with the Japan College of Rheumatology in 2004. However, issues and challenges due to changing circumstance indicate application of interferon gamma release assay (IGRA), increased variety and indication of biologics, dissemination of knowledge on strategy and system for latent tuberculosis infection (LTBI), etc. Future guideline should include 1) promoting LTBI treatment to achieve low incidence, 2) updated information on IGRAs, 3) treatment strategy and target: contact to infectious cases, immunosuppressive cases (especially HIV and patients treated with biologics), high risk groups, etc. 4) fundamental information on tuberculosis control strategies, especially DOTS. 4. Therapy for RA and tuberculosis in patients with RA and TB activated by anti-TNF treatment: Tomoshige MATSUMOTO (Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) Biologics targeting TNF, including infliximab, have brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). In 2001, tuberculosis, an ancient and also modem scourge, became spotlighted again, because Keane reported in the New England Journal of Medicine that infliximab administration induced reactivation of tuberculosis. How should we treat RA after we successfully treated tuberculosis? Decisions regarding the treatment of patients with refractory RA in the setting of active tuberculosis remain difficult. We successfully treated RA in patients with tuberculosis by anti-TNF therapy. These demonstrate that anti-TNF therapy can be considered for patients with refractory RA who have tuberculosis and in whom antituberculosis therapy can be maintained.

New and Noteworthy in Tuberculosis Diagnostics and Treatment.

PubMed

Swindells, Susan

2018-06-01

People with HIV infection with latent tuberculosis (TB) infection (LTBI) are at a 10-fold greater risk of developing active disease. Interferon gamma release assays and tuberculin skin testing have approximately 65% to 70% specificity for diagnosing LTBI in HIV-infected patients. LTBI can be successfully treated with isoniazid preventive therapy and early antiretroviral therapy (ART). Rapid molecular diagnostics have approximately 88% sensitivity and 98% specificity for identifying active TB. ART should be started early in patients with TB. A number of ART regimens are recommended in co-treatment that minimize the risk of drug-drug interactions. Although progress has been made, better diagnostics and TB regimens with lower risks of drug-drug interactions and shorter treatment durations are still needed. This article summarizes a presentation by Susan Swindells, MBBS, at the Ryan White HIV/AIDS Program Clinical Care Conference held in San Antonio in August 2017.

Modulation of dendritic cell and monocyte subsets in tuberculosis-diabetes co-morbidity upon standard tuberculosis treatment

PubMed Central

Kumar, Nathella Pavan; Moideen, Kadar; Sivakumar, Shanmugam; Menon, Pradeep A; Viswanathan, Vijay; Kornfeld, Hardy; Babu, Subash

2016-01-01

Type 2 diabetes mellitus (DM) is a major risk factor for the development of active pulmonary tuberculosis (PTB), with development of DM pandemic in countries where tuberculosis (TB) is also endemic. However, the effect of anti-TB treatment on the changes in dentritic cell (DC) and monocyte subset phenotype in TB-DM co-morbidity is not well understood. In this study, we characterized the frequency of DC and monocyte subsets in individuals with PTB with (PTB-DM) or without coincident diabetes mellitus (PTB-NDM) before, during and after completion of anti-TB treatment. PTB-DM is characterized by diminished frequencies of plasmacytoid and myeloid DCs and classical and intermediate monocytes at baseline and 2 months of anti-TB treatment but not following 6 months of treatment completion in comparison to PTB-NDM. DC and monocyte subsets exhibit significant but borderline correlation with fasting blood glucose and glycated hemoglobin levels. Finally, while minor changes in the DC and monocyte compartment were observed at 2 months of treatment, significantly increased frequencies of plasmacytoid and myeloid DCs and classical and intermediate monocytes were observed at the successful completion of anti-TB treatment. Our data show that coincident diabetes alters the frequencies of innate subset distribution of DC and monocytes in TB-DM co-morbidity and suggests that most of these changes are reversible following anti-TB therapy. PMID:27865391

Major Challenges in Clinical Management of TB/HIV Coinfected Patients in Eastern Europe Compared with Western Europe and Latin America.

PubMed

Efsen, Anne Marie W; Schultze, Anna; Post, Frank A; Panteleev, Alexander; Furrer, Hansjakob; Miller, Robert F; Losso, Marcelo H; Toibaro, Javier; Skrahin, Aliaksandr; Miro, Jose M; Caylà, Joan A; Girardi, Enrico; Bruyand, Mathias; Obel, Niels; Podlekareva, Daria N; Lundgren, Jens D; Mocroft, Amanda; Kirk, Ole

2015-01-01

Rates of TB/HIV coinfection and multi-drug resistant (MDR)-TB are increasing in Eastern Europe (EE). We aimed to study clinical characteristics, factors associated with MDR-TB and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients in EE, Western Europe (WE) and Latin America (LA). Between January 1, 2011, and December 31, 2013, 1413 TB/HIV patients (62 clinics in 19 countries in EE, WE, Southern Europe (SE), and LA) were enrolled. Significant differences were observed between EE (N = 844), WE (N = 152), SE (N = 164), and LA (N = 253) in the proportion of patients with a definite TB diagnosis (47%, 71%, 72% and 40%, p<0.0001), MDR-TB (40%, 5%, 3% and 15%, p<0.0001), and use of combination antiretroviral therapy (cART) (17%, 40%, 44% and 35%, p<0.0001). Injecting drug use (adjusted OR (aOR) = 2.03 (95% CI 1.00-4.09), prior anti-TB treatment (3.42 (1.88-6.22)), and living in EE (7.19 (3.28-15.78)) were associated with MDR-TB. Among 585 patients with drug susceptibility test (DST) results, the empiric (i.e. without knowledge of the DST results) anti-TB treatment included ≥3 active drugs in 66% of participants in EE compared with 90-96% in other regions (p<0.0001). In EE, TB/HIV patients were less likely to receive a definite TB diagnosis, more likely to house MDR-TB and commonly received empiric anti-TB treatment with reduced activity. Improved management of TB/HIV patients in EE requires better access to TB diagnostics including DSTs, empiric anti-TB therapy directed at both susceptible and MDR-TB, and more widespread use of cART.

Innovative Tuberculosis Symposium held during Cuba Salud 2015.

PubMed

Chapman, Helena J; Armas Pérez, Luisa

2016-12-01

The fourth Tuberculosis (TB) Symposium, held during the Cuba Salud 2015 International Convention, highlighted advancements in research on TB and Mycobacterium tuberculosis (Mtb) by interdisciplinary teams from academic and federal institutions in Cuba, Colombia, Mexico, and the Dominican Republic. Delegates focused on the targets presented in the World Health Organization End TB Strategy for 2016-2035 and elaborated on four primary themes: 1) attention to vulnerable populations such as immunocompromised individuals, health care workers, and residents of long-term institutions such as prisons and nursing homes; 2) identification of active and latent TB cases through contact investigations; 3) spread and control of drug-resistant Mtb strains; and 4) advancements in the development of novel vaccines or "booster" immunizations. This international TB forum served as a platform for experts in diverse disciplines in these Latin American countries to discuss challenges faced by TB research and control programs, proposing novel research initiatives and promoting collaborative teamwork strategies for TB elimination. In solidarity, collaborative efforts in TB control require identification of symptomatic individuals, rapid diagnostic testing for TB, drug susceptibility assays on Mtb strains, and management that provide universal and gratuitous access to directly observed short-course therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

The global dynamics of diabetes and tuberculosis: the impact of migration and policy implications.

PubMed

Girardi, Enrico; Sañé Schepisi, Monica; Goletti, Delia; Bates, Matthew; Mwaba, Peter; Yeboah-Manu, Dorothy; Ntoumi, Francine; Palmieri, Fabrizio; Maeurer, Markus; Zumla, Alimuddin; Ippolito, Giuseppe

2017-03-01

The convergence between tuberculosis (TB) and diabetes mellitus (DM) will represent a major public health challenge in the near future. DM increases the risk of developing TB by two to three times and also increases the risk of TB treatment failure, relapse, and death. The global prevalence of DM is predicted to rise significantly in the next two decades, particularly in some of the low- and middle-income countries with the highest TB burden. Migration may add further complexity to the effort to control the impact on TB of the growing DM pandemic. Migration may increase the risk of DM, although the magnitude of this association varies according to country of origin and ethnic group, due to genetic factors and lifestyle differences. Migrants with TB may have an increased prevalence of DM compared to the native population, and the risk of TB among persons with DM may be higher in migrants than in autochthonous populations. Screening for DM among migrants, screening migrants with DM for active and latent TB, and improving access to DM care, could contribute to mitigate the effects of DM on TB. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Role of routine abdominal ultrasonography in intensified tuberculosis case finding algorithms at HIV clinics in high TB burden settings.

PubMed

Spalgais, Sonam; Agarwal, Upasna; Sarin, Rohit; Chauhan, Devesh; Yadav, Anita; Jaiswal, Anand

2017-05-18

High proportion of TB in people living with HIV (PLHIV) is undiagnosed. Due to this active TB case finding is recommended for HIV clinics in high TB burden countries. Presently sputum examination and chest radiography are frontline tests recommended for HIV infected TB presumptives. Abdominal TB which occurs frequently in PLHIV may be missed even by existing programmatic intensified case finding protocols. This study evaluated the routine use of ultrasonography (USG) for active case finding of abdominal TB in HIV clinics. Retrospective analysis of eight years' data from an HIV Clinic in a TB hospital in India. Patients underwent chest x-ray, sputum examination, USG abdomen and routine blood tests at entry to HIV care. Case forms were scrutinized for diagnosis of TB, USG findings and CD4 cell counts. Abdominal TB was classified as probable or possible TB. Probable TB was based on presence of two major USG (abdomen) findings suggestive of active TB, or one major USG finding with at least two minor USG findings or at least two symptoms, or any USG finding with microbiologically confirmed active TB at another site. Possible TB was based on the presence of one major USG finding, or the presence of two minor USG findings with at least two symptoms. Bacteriological confirmation was not obtained. Eight hundred and eighty-nine people PLHIV underwent a baseline USG abdomen. One hundred and thirteen of 340 cases already diagnosed with TB and 87 of the 91 newly diagnosed with TB at time of HIV clinic registration had abdominal TB. Non-abdominal symptoms like weight loss, fever and cough were seen in 53% and 22% cases had no symptoms at all. Enlarged abdominal lymph nodes with central caseation, ascitis, splenic microabsesses, bowel thickening and hepatosplenomegaly were the USG findings in these cases. Abdominal TB is a frequent TB site in PLHIV presenting with non-abdominal symptoms. It can be easily detected on basis of features seen on a simple abdominal ultrasound. Abdominal USG should be essential part of intensified TB case finding algorithms for HIV infected people living in high TB burden settings.

Risk factors for treatment default in close contacts with latent tuberculous infection.

PubMed

Fiske, C T; Yan, F-X; Hirsch-Moverman, Y; Sterling, T R; Reichler, M R

2014-04-01

1) To characterize risk factors for non-completion of latent tuberculous infection treatment (LTBIT), and 2) to assess the impact of LTBIT regimens on subsequent risk of tuberculosis (TB). Close contacts of adults aged ⩾15 years with pulmonary TB were prospectively enrolled in a multi-center study in the United States and Canada from January 2002 to December 2006. Close contacts of TB patients were screened and cross-matched with TB registries to identify those who developed active TB. Of 3238 contacts screened, 1714 (53%) were diagnosed with LTBI. Preventive treatment was recommended in 1371 (80%); 1147 (84%) initiated treatment, of whom 723 (63%) completed it. In multivariate analysis, study site, initial interview sites other than a home or health care setting and isoniazid preventive treatment (IPT) were significantly associated with non-completion of LTBIT. Fourteen TB cases were identified in contacts, all of whom initiated IPT: two TB cases among persons who received ⩾6 months of IPT (66 cases/100 000 person-years [py]), and nine among those who received 0-5 months (median 2 months) of IPT (792 cases/100 000 py, P < 0.001); data on duration of IPT were not available for three cases. Only 53% (723/1371) of close contacts for whom IPT was recommended actually completed treatment. Close contacts were significantly less likely to complete LTBIT if they took IPT. Less than 6 months of IPT was associated with increased risk of active TB.

The effect of micronutrient supplementation on active TB incidence early in HIV infection in Botswana

PubMed Central

Campa, Adriana; Baum, Marianna K; Bussmann, Hermann; Martinez, Sabrina Sales; Farahani, Mansour; van Widenfelt, Erik; Moyo, Sikhulile; Makhema, Joseph; Essex, Max; Marlink, Richard

2017-01-01

Background Coinfection with active tuberculosis (TB) is one of the leading causes of death in people living with HIV (PLWH) in Africa. This investigation explores the role of micronutrient supplementation in preventing active TB in PLWH. Methods A randomized trial of nutritional supplementation was conducted among antiretroviral- naïve (without previous antiretroviral treatment [ART]) HIV-infected people in Botswana between 2004 and 2009. The study had a factorial design with four arms: the selenium (Se) alone arm, the multivitamins (MVT) alone arm that contained vitamin B complex and vitamins C and E, the combined Se+MVT group and the placebo group. Those participants with prior or current active TB were excluded, as were participants with advanced HIV disease (CD4 <250 cells/μL) or who had already qualified for ART. HIV-positive adults (N=878) were followed monthly for study pill dispensation, every 3 months for CD4 cell count and every 6 months for viral load during 24 months or until they were started on ART. Results The participants' characteristics were not significantly different among the four groups at baseline. Supplementation with Se alone (hazard ratio =0.20, 95% confidence interval: 0.04, 0.95, P=0.043) and the two combined SE groups (Se and Se+MVT) had significantly lower risk of developing incident TB disease compared with placebo in multivariate adjusted models (hazard ratio=0.32, 95% confidence interval: 0.11, 0.93, P=0.036). Multivitamins alone did not affect the incidence of TB. Isoniazid preventive therapy was received by 12.2% of participants, a rate that was not significantly different among the four study arms (P=0.122) and the newly diagnosed cases. Conclusion Se supplementation, alone and with MVT, decreased the incidence of TB disease in PLWH who were ART-naïve. Supplementation with these micronutrients should be considered in HIV infection, prior to ART, in areas where TB and malnutrition are endemic. PMID:29187783

Operational research within a Global Fund supported tuberculosis project in India: why, how and its contribution towards change in policy and practice

PubMed Central

Sagili, Karuna D; Satyanarayana, Srinath; Chadha, Sarabjit S; Wilson, Nevin C; Kumar, Ajay M V; Oeltmann, John E; Chadha, Vineet K; Nagaraja, Sharath Burugina; Ghosh, Smita; Q Lo, Terrence; Volkmann, Tyson; Willis, Matthew; Shringarpure, Kalpita; Reddy, Ravichandra Chinnappa; Kumar, Prahlad; Nair, Sreenivas A; Rao, Raghuram; Yassin, Mohammed; Mwangala, Perry; Zachariah, Rony; Tonsing, Jamhoih; Harries, Anthony D; Khaparde, Sunil

2018-01-01

ABSTRACT Background: The Global Fund encourages operational research (OR) in all its grants; however very few reports describe this aspect. In India, Project Axshya was supported by a Global Fund grant to improve the reach and visibility of the government Tuberculosis (TB) services among marginalised and vulnerable communities. OR was incorporated to build research capacity of professionals working with the national TB programme and to generate evidence to inform policies and practices. Objectives: To describe how Project Axshya facilitated building OR capacity within the country, helped in addressing several TB control priority research questions, documented project activities and their outcomes, and influenced policy and practice. Methods: From September 2010 to September 2016, three key OR-related activities were implemented. First, practical output-oriented modular training courses were conducted (n = 3) to build research capacity of personnel involved in the TB programme, co-facilitated by The Union, in collaboration with the national TB programme, WHO country office and CDC, Atlanta. Second, two large-scale Knowledge, Attitude and Practice (KAP) surveys were conducted at baseline and mid-project to assess the changes pertaining to TB knowledge, attitudes and practices among the general population, TB patients and health care providers over the project period. Third, studies were conducted to describe the project’s core activities and outcomes. Results: In the training courses, 44 participant teams were supported to develop research protocols on topics of national priority, resulting in 28 peer-reviewed scientific publications. The KAP surveys and description of project activities resulted in 14 peer-reviewed publications. Of the published papers at least 12 have influenced change in policy or practice. Conclusions: OR within a Global Fund supported TB project has resulted in building OR capacity, facilitating research in areas of national priority and influencing policy and practice. We believe this experience will provide guidance for undertaking OR in Global Fund projects. PMID:29553308

Operational research within a Global Fund supported tuberculosis project in India: why, how and its contribution towards change in policy and practice.

PubMed

Sagili, Karuna D; Satyanarayana, Srinath; Chadha, Sarabjit S; Wilson, Nevin C; Kumar, Ajay M V; Moonan, Patrick K; Oeltmann, John E; Chadha, Vineet K; Nagaraja, Sharath Burugina; Ghosh, Smita; Q Lo, Terrence; Volkmann, Tyson; Willis, Matthew; Shringarpure, Kalpita; Reddy, Ravichandra Chinnappa; Kumar, Prahlad; Nair, Sreenivas A; Rao, Raghuram; Yassin, Mohammed; Mwangala, Perry; Zachariah, Rony; Tonsing, Jamhoih; Harries, Anthony D; Khaparde, Sunil

2018-01-01

The Global Fund encourages operational research (OR) in all its grants; however very few reports describe this aspect. In India, Project Axshya was supported by a Global Fund grant to improve the reach and visibility of the government Tuberculosis (TB) services among marginalised and vulnerable communities. OR was incorporated to build research capacity of professionals working with the national TB programme and to generate evidence to inform policies and practices. To describe how Project Axshya facilitated building OR capacity within the country, helped in addressing several TB control priority research questions, documented project activities and their outcomes, and influenced policy and practice. From September 2010 to September 2016, three key OR-related activities were implemented. First, practical output-oriented modular training courses were conducted (n = 3) to build research capacity of personnel involved in the TB programme, co-facilitated by The Union, in collaboration with the national TB programme, WHO country office and CDC, Atlanta. Second, two large-scale Knowledge, Attitude and Practice (KAP) surveys were conducted at baseline and mid-project to assess the changes pertaining to TB knowledge, attitudes and practices among the general population, TB patients and health care providers over the project period. Third, studies were conducted to describe the project's core activities and outcomes. In the training courses, 44 participant teams were supported to develop research protocols on topics of national priority, resulting in 28 peer-reviewed scientific publications. The KAP surveys and description of project activities resulted in 14 peer-reviewed publications. Of the published papers at least 12 have influenced change in policy or practice. OR within a Global Fund supported TB project has resulted in building OR capacity, facilitating research in areas of national priority and influencing policy and practice. We believe this experience will provide guidance for undertaking OR in Global Fund projects.

Distance Learning Course for Healthcare Professionals: Continuing Education in Tuberculosis.

PubMed

Cabral, Vagner Kunz; Valentini, Dirceu Felipe; Rocha, Marcos Vinícius Vieira; de Almeida, Carlos Podalírio Borges; Cazella, Sílvio Cesar; Silva, Denise Rossato

2017-12-01

Continuing education of healthcare workers (HCWs) is an essential strategy for the control of tuberculosis (TB) transmission, enabling HCWs in early detection and appropriate treatment of TB cases. We developed a distance learning (DL) course on TB for nurses. We conducted a quasi-experimental before and after study to evaluate the DL community at the participant's learning level. In addition, to evaluate the DL community at the level of participant satisfaction, a cross-sectional study was carried out after the course. Nurses involved in active inpatient or outpatient care of patients were recruited to participate in the study. Sixty-six participants started and completed the course and they were included in the analysis. The overall mean pretest and post-test scores were 10.3 ± 2.2 and 11.4 ± 2.7, respectively. Participants increased their knowledge to a statistically significant degree (p < 0.0001). At baseline, the frequency of correct answers was very low in some questions: number of people infected by Mycobacterium tuberculosis in the world (10.6%); number of TB cases in Brazil (36.4%); contagiousness of latent TB infection (LTBI) (28.8%); and definition of active case finding (45.5%). Course feedback was mostly positive, with majority of users saying they were satisfied or totally satisfied. A brief DL course on TB was associated with some improvement in knowledge among nurses. The baseline knowledge was low regarding TB epidemiologic data, concepts on LTBI, and active case finding. This finding emphasizes the need to further improve the competencies and knowledge of nurses.

Pyrimidin-2(1H)-ones based inhibitors of Mycobacterium tuberculosis orotate phosphoribosyltransferase.

PubMed

Breda, Ardala; Machado, Pablo; Rosado, Leonardo Astolfi; Souto, André Arigony; Santos, Diógenes Santiago; Basso, Luiz Augusto

2012-08-01

Tuberculosis (TB) is an ancient human chronic infectious disease caused mainly by Mycobacterium tuberculosis. The emergence of strains resistant to first and second line anti-TB drugs, associated with the increasing number of TB cases among HIV positive subjects, and the large number of individuals infected with latent bacilli have urged the development of new strategies to treat TB. Enzymes of nucleotide metabolism pathways provide promising molecular targets for the development of drugs, aiming at both active and latent TB. The orotate phosphoribosyltransferase (OPRT) enzyme catalyzes the synthesis of orotidine 5'-monophosphate from 5'-phospho-α-d-ribose 1'-diphosphate and orotic acid, in the de novo pyrimidine synthesis pathway. Based on the kinetic mechanism and molecular properties, here we describe the design, selection and synthesis of substrate analogs with inhibitory activity of M. tuberculosis OPRT (MtOPRT) enzyme. Steady-state kinetic measurements were employed to determine the mode of inhibition of commercially available and chemically derived compounds. The 6-Hydroxy-2-oxo-1,2-dihydropyridine-4-carboxylic acid (6) chemical compound and its derivative, 3-Benzylidene-2,6-dioxo-1,2,3,6-tetrahydropyridine-4-carboxylic acid (13), showed enzyme inhibition constants in the submicromolar range. Isothermal titration calorimetry data indicated that binding of both compounds to MtOPRT have negative enthalpy and favorable Gibbs free energy probably due to their high complementarity to the enzyme's binding pocket. Improvement of compound 13 hydrophobic character by addition of an aromatic ring substituent resulted in entropic optimization, reflected on a thermodynamic discrimination profile characteristic of high affinity ligands. These inhibitors represent lead compounds for further development of MtOPRT inhibitors with increased potency, which may be tested as anti-TB agents. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Reading a Story: Different Degrees of Learning in Different Learning Environments.

PubMed

Giannini, Anna Maria; Cordellieri, Pierluigi; Piccardi, Laura

2017-01-01

The learning environment in which material is acquired may produce differences in delayed recall and in the elements that individuals focus on. These differences may appear even during development. In the present study, we compared three different learning environments in 450 normally developing 7-year-old children subdivided into three groups according to the type of learning environment. Specifically, children were asked to learn the same material shown in three different learning environments: reading illustrated books (TB); interacting with the same text displayed on a PC monitor and enriched with interactive activities (PC-IA); reading the same text on a PC monitor but not enriched with interactive narratives (PC-NoIA). Our results demonstrated that TB and PC-NoIA elicited better verbal memory recall. In contrast, PC-IA and PC-NoIA produced higher scores for visuo-spatial memory, enhancing memory for spatial relations, positions and colors with respect to TB. Interestingly, only TB seemed to produce a deeper comprehension of the story's moral. Our results indicated that PC-IA offered a different type of learning that favored visual details. In this sense, interactive activities demonstrate certain limitations, probably due to information overabundance, emotional mobilization, emphasis on images and effort exerted in interactive activities. Thus, interactive activities, although entertaining, act as disruptive elements which interfere with verbal memory and deep moral comprehension.

Reading a Story: Different Degrees of Learning in Different Learning Environments

PubMed Central

Giannini, Anna Maria; Cordellieri, Pierluigi; Piccardi, Laura

2017-01-01

The learning environment in which material is acquired may produce differences in delayed recall and in the elements that individuals focus on. These differences may appear even during development. In the present study, we compared three different learning environments in 450 normally developing 7-year-old children subdivided into three groups according to the type of learning environment. Specifically, children were asked to learn the same material shown in three different learning environments: reading illustrated books (TB); interacting with the same text displayed on a PC monitor and enriched with interactive activities (PC-IA); reading the same text on a PC monitor but not enriched with interactive narratives (PC-NoIA). Our results demonstrated that TB and PC-NoIA elicited better verbal memory recall. In contrast, PC-IA and PC-NoIA produced higher scores for visuo-spatial memory, enhancing memory for spatial relations, positions and colors with respect to TB. Interestingly, only TB seemed to produce a deeper comprehension of the story’s moral. Our results indicated that PC-IA offered a different type of learning that favored visual details. In this sense, interactive activities demonstrate certain limitations, probably due to information overabundance, emotional mobilization, emphasis on images and effort exerted in interactive activities. Thus, interactive activities, although entertaining, act as disruptive elements which interfere with verbal memory and deep moral comprehension. PMID:29085296

Anti-mycobacterial activity of polyketides from Penicillium sp. endophyte isolated from Garcinia nobilis against Mycobacteriumsmegmatis.

PubMed

Jouda, Jean Bosco; Mawabo, Isabelle Kamga; Notedji, Augustin; Mbazoa, Céline Djama; Nkenfou, Jean; Wandji, Jean; Nkenfou, Céline Nguefeu

2016-06-01

According to estimates by the World Health Organization, there were 9.6 million new tuberculosis (TB) cases in 2014: 5.4 million among men, 3.2 million among women, and 1.0 million among children. There were also 1.5 million TB deaths. Although there are potent anti-TB molecules, the misuse of these drugs in addition to inconsistent or partial treatment have led to the development of multidrug-resistant TB and extensively drug-resistant TB. It is established that plants harbor microorganisms, collectively known as endophytes, which also produce metabolites. Exploring the as-yet untapped natural products from the endophytes increases the chances of finding novel and active compounds. The present study was aimed to investigate the antimycobacterial activity of the crude extract and compounds isolated from Penicillium sp. endophyte associated with Garcinia nobilis against Mycobacterium smegmatis. Liquid culture obtained from the fermentation of Penicillium sp. was extracted using ethylacetate and the liquid chromatography-mass spectrometry monitored fractionation of crude extracts yielded six compounds. Their structures were elucidated with spectroscopic analyses including two-dimensional nuclear magnetic resonance, high resolution mass spectrometry by dereplication using Antibase, and by comparison to literature data. All compounds and the crude extract from the liquid medium were evaluated for their antimycobacterial activity against M. smegmatis. In this study, the activity of penialidins A-C (1-3), citromycetin (4), p-hydroxy phenyl glyoxalaldoxime (5), and Brefeldin A (6) were tested against nonpathogenic M. smegmatis. Penialidin C was the most active compound with a minimum inhibitory concentration of 15.6μg/mL. Isolated compounds from Penicillium sp. harbored in G. nobilis exhibited promising antimycobacterial activity against M. smegmatis thus supporting the immensity of the potential of antimycobacterial drug discovery from endophytes from medicinal plants. Penialidin C could further be investigated for antimycobacterial drug development. Copyright © 2016 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

Tuberculosis infection testing in HIV-positive men who have sex with men from Xi'an China.

PubMed

Xin, H N; Li, X W; Zhang, L; Li, Z; Zhang, H R; Yang, Y; Li, M F; Feng, B X; Li, H J; Gao, L

2017-02-01

In individuals with latent tuberculosis (TB) infection, those living with human immunodeficiency virus (HIV) had a 20-37 times higher risk of developing active TB compared to those without HIV infection. Systematic testing and treatment of latent TB infection are priorities in HIV-infected persons. In China, the prevalence of HIV infection in men who have sex with men (MSM) has gradually increased in the past decade. However, the prevalence of TB infection has been studied sparsely in HIV-infected MSM. Hence, we conducted a pilot study in MSM living with HIV infection in Xi'an city to evaluate TB infection status by means of interferon-γ release assay (IGRA). A total of 182 HIV-infected MSM were included in this study, the prevalence of IGRA positivity was observed to be 8·79% (16/182). IGRA quantitative results were not statistically influenced by the CD4 cell counts of the study participants. However, IGRA positivity was found to be lower than our previously reported data from the general population. This suggests that immunological deficiency might decrease the sensitivity of IGRA and thus increase the number of false negatives. Our primary results, suggesting systematic testing and treatment of latent TB infection together with active case-finding, were equally important for TB control in persons living with HIV infection.

TEOSINTE BRANCHED1 Regulates Inflorescence Architecture and Development in Bread Wheat (Triticum aestivum)[OPEN

PubMed Central

Greenwood, Julian R.; Bencivenga, Stefano; Cockram, James; Cavanagh, Colin; Swain, Steve M.

2018-01-01

The flowers of major cereals are arranged on reproductive branches known as spikelets, which group together to form an inflorescence. Diversity for inflorescence architecture has been exploited during domestication to increase crop yields, and genetic variation for this trait has potential to further boost grain production. Multiple genes that regulate inflorescence architecture have been identified by studying alleles that modify gene activity or dosage; however, little is known in wheat. Here, we show TEOSINTE BRANCHED1 (TB1) regulates inflorescence architecture in bread wheat (Triticum aestivum) by investigating lines that display a form of inflorescence branching known as “paired spikelets.” We show that TB1 interacts with FLOWERING LOCUS T1 and that increased dosage of TB1 alters inflorescence architecture and growth rate in a process that includes reduced expression of meristem identity genes, with allelic diversity for TB1 found to associate genetically with paired spikelet development in modern cultivars. We propose TB1 coordinates formation of axillary spikelets during the vegetative to floral transition and that alleles known to modify dosage or function of TB1 could help increase wheat yields. PMID:29444813

TEOSINTE BRANCHED1 Regulates Inflorescence Architecture and Development in Bread Wheat (Triticum aestivum).

PubMed

Dixon, Laura E; Greenwood, Julian R; Bencivenga, Stefano; Zhang, Peng; Cockram, James; Mellers, Gregory; Ramm, Kerrie; Cavanagh, Colin; Swain, Steve M; Boden, Scott A

2018-03-01

The flowers of major cereals are arranged on reproductive branches known as spikelets, which group together to form an inflorescence. Diversity for inflorescence architecture has been exploited during domestication to increase crop yields, and genetic variation for this trait has potential to further boost grain production. Multiple genes that regulate inflorescence architecture have been identified by studying alleles that modify gene activity or dosage; however, little is known in wheat. Here, we show TEOSINTE BRANCHED1 ( TB1 ) regulates inflorescence architecture in bread wheat ( Triticum aestivum ) by investigating lines that display a form of inflorescence branching known as "paired spikelets." We show that TB1 interacts with FLOWERING LOCUS T1 and that increased dosage of TB1 alters inflorescence architecture and growth rate in a process that includes reduced expression of meristem identity genes, with allelic diversity for TB1 found to associate genetically with paired spikelet development in modern cultivars. We propose TB1 coordinates formation of axillary spikelets during the vegetative to floral transition and that alleles known to modify dosage or function of TB1 could help increase wheat yields. © 2018 American Society of Plant Biologists. All rights reserved.

Evaluation of the Tuberculosis Infection Control Training Center, Tajikistan, 2014–2015

PubMed Central

Scott, C.; Mangan, J.; Tillova, Z.; Jensen, P. A.; Ahmedov, S.; Ismoilova, J.; Trusov, A.

2017-01-01

SUMMARY SETTING Training center on tuberculosis (TB) infection control (IC) for health care workers in the Central Asian Republics region. OBJECTIVE To assess the effects of TB IC training courses conducted at the Tuberculosis Infection Control Training Center in Machiton, Tajikistan. DESIGN Participants who participated in training (n = 89) during the first year of operation (April 2014–February 2015) were invited to participate in a post-training interview. RESULTS Of the 89 participants, 84 (94%) completed the interview and expressed satisfaction with the training. Eighty (95%) participants reported meeting with workplace leadership to discuss the training. Of these, 69 (85%) reported discussing changes required to meet TB IC standards. Self-reported changes in TB IC practices at work facilities post training included the creation of TB IC committees, designation of a TB IC focal person, TB IC planning, policies to separate infectious patients in waiting rooms, provision of masks for infectious patients, development of cough etiquette policies, improved glove availability, hand hygiene programs, and TB IC posters in waiting rooms. CONCLUSIONS Participant satisfaction and reported changes in TB IC activities illustrate the potential of these training courses to improve TB IC in the region. Future training courses may be tailored to specific audiences using a structured conceptual framework to impact administration, budgeting, and facilities management of TB IC practices. PMID:28399974

Perceptions of tuberculosis among immigrants and refugees at an adult education center: a community-based participatory research approach.

PubMed

Wieland, Mark L; Weis, Jennifer A; Yawn, Barbara P; Sullivan, Susan M; Millington, Kendra L; Smith, Christina M; Bertram, Susan; Nigon, Julie A; Sia, Irene G

2012-02-01

English as a Second Language programs serve large foreign-born populations in the US with elevated risks of tuberculosis (TB), yet little is known about TB perceptions in these settings. Using a community-based participatory research approach, we elicited perceptions about TB among immigrant and refugee learners and staff at a diverse adult education center. Community partners were trained in focus groups moderation. Ten focus groups were conducted with 83 learners and staff. Multi-level, team-based qualitative analysis was conducted to develop themes that informed a model of TB perceptions among participants. Multiple challenges with TB control and prevention were identified. There were a variety of misperceptions about transmission of TB, and a lack of knowledge about latent TB. Feelings and perceptions related to TB included secrecy, shame, fear, and isolation. Barriers to TB testing include low awareness, lack of knowledge about latent TB, and the practical considerations of transportation, cost, and work schedule conflicts. Barriers to medication use include suspicion of generic medications and perceived side effects. We posit adult education centers with large immigrant and refugee populations as excellent venues for TB prevention, and propose several recommendations for conducting these programs. Content should dispel the most compelling misperceptions about TB transmission while clarifying the difference between active and latent disease. Learners should be educated about TB in the US and that it is curable. Finally, TB programs that include learners and staff in their design and implementation provide greater opportunity for overcoming previously unrecognized barriers.

The strategic framework of tuberculosis control and prevention in the elderly: a scoping review towards End TB targets.

PubMed

Li, Jun; Chung, Pui-Hong; Leung, Cyrus L K; Nishikiori, Nobuyuki; Chan, Emily Y Y; Yeoh, Eng-Kiong

2017-06-01

With the rapid pace of population ageing, tuberculosis (TB) in the elderly increasingly becomes a public health challenge. Despite the increasing burden and high risks for TB in the elderly, targeted strategy has not been well understood and evaluated. We undertook a scoping review to identify current TB strategies, research and policy gaps in the elderly and summarized the results within a strategic framework towards End TB targets. Databases of Embase, MEDLINE, Global health and EBM reviews were searched for original studies, review articles, and policy papers published in English between January 1990 and December 2015. Articles examining TB strategy, program, guideline or intervention in the elderly from public health perspective were included.Nineteen articles met the inclusion criteria. Most of them were qualitative studies, issued in high- and middle-income countries and after 2000. To break the chain of TB transmission and reactivation in the elderly, infection control, interventions of avoiding delay in diagnosis and containment are essential for preventing transmission, especially in elderly institutions and aged immigrants; screening of latent TB infection and preventive therapy had effective impacts on reducing the risk of reactivation and should be used less reluctantly in older people; optimizing early case-finding with a high index of suspicion, systematic screening for prioritized high-risk groups, initial empirical and adequate follow-up treatment with close monitoring and evaluation, as well as enhanced programmatic management are fundamental pillars for active TB elimination. Evaluation of TB epidemiology, risk factors, impacts and cost-effectiveness of interventions, adopting accurate and rapid diagnostic tools, shorter and less toxic preventive therapy, are critical issues for developing strategy in the elderly towards End TB targets.TB control strategies in the elderly were comprehensively mapped in a causal link pathway. The framework and principals identified in this study will help to evaluate and improve current program, develop targeted strategy, as well as raise more discussions on the research priority settings and policy transitions. Given the scarceness of policy and evaluated interventions, as well as the unawareness of shifting TB epidemiology and strategy especially in developing countries, the increasing need of a ready TB program for the elderly warrants further research.

An Evaluation of Passive and Active Approaches to Improve Tuberculosis Notifications in Afghanistan

PubMed Central

Sanaie, A.; Nasrat, A.; Seddiq, M. K.; Mahmoodi, S. D.; Stevens, R. H.; Creswell, J.

2016-01-01

Background In Afghanistan, improving TB case detection remains challenging. In 2014, only half of the estimated incident TB cases were notified, and notifications have decreased since peaking in 2007. Active case finding has been increasingly considered to improve TB case notifications. While access to health services has improved in Afghanistan, it remains poor and many people seeking health services won’t receive proper care. Methods From October 2011 through December 2012 we conducted three separate case finding strategies in six provinces of Afghanistan and measured impact on TB case notification. Systematically screening cough among attendees at 47 health facilities, active household contact investigation of smear-positive index TB patients, and active screening at 15 camps for internally displaced people were conducted. We collected both intervention yield and official quarterly notification data. Additional TB notifications were calculated by comparing numbers of cases notified during the intervention with those notified before the intervention, then adjusting for secular trends in notification. Results We screened 2,022,127 people for TB symptoms during the intervention, tested 59,838 with smear microscopy and detected 5,046 people with smear-positive TB. Most cases (81.7%, 4,125) were identified in health facilities while nearly 20% were found through active case finding. A 56% increase in smear-positive TB notifications was observed between the baseline and intervention periods among the 47 health facilities, where cases detected by all three strategies were notified. Discussion While most people with TB are likely to be identified through health facility screening, there are many people who remain without a proper diagnosis if outreach is not attempted. This is especially true in places like Afghanistan where access to general services is poor. Targeted active case finding can improve the number of people who are detected and treated for TB and can push towards the targets of the Stop TB Global Plan and End TB Strategy. PMID:27701446

An Evaluation of Passive and Active Approaches to Improve Tuberculosis Notifications in Afghanistan.

PubMed

Sanaie, A; Mergenthaler, C; Nasrat, A; Seddiq, M K; Mahmoodi, S D; Stevens, R H; Creswell, J

2016-01-01

In Afghanistan, improving TB case detection remains challenging. In 2014, only half of the estimated incident TB cases were notified, and notifications have decreased since peaking in 2007. Active case finding has been increasingly considered to improve TB case notifications. While access to health services has improved in Afghanistan, it remains poor and many people seeking health services won't receive proper care. From October 2011 through December 2012 we conducted three separate case finding strategies in six provinces of Afghanistan and measured impact on TB case notification. Systematically screening cough among attendees at 47 health facilities, active household contact investigation of smear-positive index TB patients, and active screening at 15 camps for internally displaced people were conducted. We collected both intervention yield and official quarterly notification data. Additional TB notifications were calculated by comparing numbers of cases notified during the intervention with those notified before the intervention, then adjusting for secular trends in notification. We screened 2,022,127 people for TB symptoms during the intervention, tested 59,838 with smear microscopy and detected 5,046 people with smear-positive TB. Most cases (81.7%, 4,125) were identified in health facilities while nearly 20% were found through active case finding. A 56% increase in smear-positive TB notifications was observed between the baseline and intervention periods among the 47 health facilities, where cases detected by all three strategies were notified. While most people with TB are likely to be identified through health facility screening, there are many people who remain without a proper diagnosis if outreach is not attempted. This is especially true in places like Afghanistan where access to general services is poor. Targeted active case finding can improve the number of people who are detected and treated for TB and can push towards the targets of the Stop TB Global Plan and End TB Strategy.

In vitro pharmacokinetic/pharmacodynamic models in anti-infective drug development: focus on TB

PubMed Central

Vaddady, Pavan K; Lee, Richard E; Meibohm, Bernd

2011-01-01

For rapid anti-tuberculosis (TB) drug development in vitro pharmacokinetic/pharmacodynamic (PK/PD) models are useful in evaluating the direct interaction between the drug and the bacteria, thereby guiding the selection of candidate compounds and the optimization of their dosing regimens. Utilizing in vivo drug-clearance profiles from animal and/or human studies and simulating them in an in vitro PK/PD model allows the in-depth characterization of antibiotic activity of new and existing antibacterials by generating time–kill data. These data capture the dynamic interplay between mycobacterial growth and changing drug concentration as encountered during prolonged drug therapy. This review focuses on important PK/PD parameters relevant to anti-TB drug development, provides an overview of in vitro PK/PD models used to evaluate the efficacy of agents against mycobacteria and discusses the related mathematical modeling approaches of time–kill data. Overall, it provides an introduction to in vitro PK/PD models and their application as critical tools in evaluating anti-TB drugs. PMID:21359155

Time-series analysis of monthly age-specific numbers of newly registered cases of active tuberculosis in Japan from 1998 to 2013.

PubMed

Kohei, Y; Sumi, A; Kobayashi, N

2016-08-01

We investigated the seasonality of age-specific tuberculosis (TB) in Japan. To allow the development of TB control strategies for different age groups we used a time-series analysis, including a spectral analysis and least squares method, to analyse the monthly age-specific numbers of newly registered cases of all forms of active TB in Japan from January 1998 to December 2013. The time-series data are reported in 10-year age groups: 0-9, 10-19, …, 70-79, and ⩾80 years. We defined the contribution ratio of the 1-year cycle, Q 1, as the contribution of the amplitude of a 1-year cycle to the whole amplitude of the time-series data. The Q 1 values in the age groups corresponding to adolescence and middle life (10-39 years) and old age (⩾70 years) were high. The peaks in the active TB epidemics for the ⩾70 years age group occurred in August and September, 1-2 months behind the peaks for the 10-39 years age group (June and July). An active TB epidemic might be attributable to travel by public transport and irregular employment in the 10-39 years age group and immune system suppression by low winter temperatures in the ⩾70 years age group.

Mycobacterium tuberculosis Lipolytic Enzymes as Potential Biomarkers for the Diagnosis of Active Tuberculosis

PubMed Central

Brust, Belinda; Lecoufle, Mélanie; Tuaillon, Edouard; Dedieu, Luc; Canaan, Stéphane; Valverde, Viviane; Kremer, Laurent

2011-01-01

Background New diagnosis tests are urgently needed to address the global tuberculosis (TB) burden and to improve control programs especially in resource-limited settings. An effective in vitro diagnostic of TB based on serological methods would be regarded as an attractive progress because immunoassays are simple, rapid, inexpensive, and may offer the possibility to detect cases missed by standard sputum smear microscopy. However, currently available serology tests for TB are highly variable in sensitivity and specificity. Lipolytic enzymes have recently emerged as key factors in lipid metabolization during dormancy and/or exit of the non-replicating growth phase, a prerequisite step of TB reactivation. The focus of this study was to analyze and compare the potential of four Mycobacterium tuberculosis lipolytic enzymes (LipY, Rv0183, Rv1984c and Rv3452) as new markers in the serodiagnosis of active TB. Methods Recombinant proteins were produced and used in optimized ELISA aimed to detect IgG and IgM serum antibodies against the four lipolytic enzymes. The capacity of the assays to identify infection was evaluated in patients with either active TB or latent TB and compared with two distinct control groups consisting of BCG-vaccinated blood donors and hospitalized non-TB individuals. Results A robust humoral response was detected in patients with active TB whereas antibodies against lipolytic enzymes were infrequently detected in either uninfected groups or in subjects with latent infection. High specifity levels, ranging from 93.9% to 97.5%, were obtained for all four antigens with sensitivity values ranging from 73.4% to 90.5%, with Rv3452 displaying the highest performances. Patients with active TB usually exhibited strong IgG responses but poor IgM responses. Conclusion These results clearly indicate that the lipolytic enzymes tested are strongly immunogenic allowing to distinguish active from latent TB infections. They appear as potent biomarkers providing high sensitivity and specificity levels for the immunodiagnosis of active TB. PMID:21966416

Difference Between Latent TB Infection and Active TB Disease

MedlinePlus

... chest x-ray, or positive sputum smear or culture • • Has active TB bacteria in his/her body • • Usually feels sick and may have symptoms such as coughing, fever, and weight loss • • May spread TB bacteria to others • • Needs treatment ...

Decreased serum 5-oxoproline in TB patients is associated with pathological damage of the lung.

PubMed

Che, Nanying; Cheng, Jianhua; Li, Haijing; Zhang, Zhiguo; Zhang, Xuxia; Ding, Zhixin; Dong, Fangting; Li, Chuanyou

2013-08-23

Tuberculosis (TB) is a serious world-wide health problem, causing millions of deaths every year. Metabolomics is a relatively new approach to identify disease specific biomarkers. However, there is little information available on metabolite biomarkers in TB. In this study, we used gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS) to identify serum metabolite biomarkers associated with the active state of TB. Potential biomarkers were selected by comparing serum metabolites in 10 healthy donors with 10TB patients, and in 6TB patients before and after treatment. Selected biomarkers were then validated using a larger population of samples from 120 healthy donors and 120TB patients derived from different clinical backgrounds The 5-oxoproline level was consistently low in patients with active TB. Further validation in larger population of clinical samples showed that 5-oxoproline was associated with pathological damage of the lung but not with age, sex, or bacterial burden in TB patients. Serum 5-oxoproline may be a useful biomarker for active TB and pathological damage of the lung. Copyright © 2013 Elsevier B.V. All rights reserved.

Electrocatalysis of carbon black- or poly(diallyldimethylammonium chloride)-functionalized activated carbon nanotubes-supported Pd-Tb towards methanol oxidation in alkaline media

NASA Astrophysics Data System (ADS)

Wang, Li; Wang, Yi; Li, An; Yang, Yunshang; Tang, Qinghu; Cao, Hongbin; Qi, Tao; Li, Changming

2014-07-01

The Pd-Tb/C catalysts with different Pd/Tb ratios were synthesized by a simple simultaneous reduction reaction with sodium borohydride in aqueous solution. The structure and morphology of those catalysts had been characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM). The electrocatalytic performance of those catalysts for methanol oxidation in alkaline media was investigated using cyclic voltammetry (CV), linear sweep voltammetry (LSV) and CO stripping experiments. It is found that the 20%Pd-1%Tb/C catalyst has a higher catalytic activity than the 20%Pd/C catalyst, but the effect of Tb cannot be explained by a bi-functional mechanism. According to the X-Ray photoelectron spectroscopy (XPS) analyses, it is suggested that the higher content of metallic Pd caused by the addition of Tb contributes to the better catalytic activity of 20%Pd-1%Tb/C. Based on the good electrocatalytic performance of 20%Pd-1%Tb/C, the 20%Pd-1%Tb catalyst supported on poly(diallyldimethylammonium chloride) (PDDA)-functionalized activated carbon nanotubes was prepared, and it exhibits a better catalytic activity. The improvement mainly results from the further increase of metallic Pd due to the presence of PDDA.

Development of tuberculosis infection control guidelines in a pediatric HIV clinic in sub-Saharan Africa.

PubMed

Carlucci, J G; Jin, L; Sanders, J E; Mohapi, E Q; Mandalakas, A M

2015-03-21

A well-established pediatric human immunodeficiency virus (HIV) clinic in Lesotho with initial infection control (IC) measures prioritizing blood-borne disease. In line with international recommendations, services have been expanded to include the management of patients with tuberculosis (TB). The creation of comprehensive IC guidelines with an emphasis on TB has become a priority. To provide a model for developing and implementing IC guidelines in ambulatory care facilities in limited-resource settings with high HIV and TB prevalence. Activities: An IC plan that includes guidance covering both general IC measures and TB-specific guidelines was created by integrating local and international recommendations and emphasizing the importance of administrative measures, environmental controls, and disease-specific precautions. An interdisciplinary committee was established to oversee its implementation, monitoring, and evaluation. Development and implementation of IC guidelines in resource-limited settings are feasible and should be a priority in high HIV and TB prevalence areas. Education should be the cornerstone of such endeavors. Many interventions can be implemented with minimal expertise and material resources. Administrative support and institutional investment are essential to the sustainability of an effective IC program.

Elevated body temperature during sleep in orexin knockout mice

PubMed Central

Mochizuki, Takatoshi; Klerman, Elizabeth B.; Sakurai, Takeshi; Scammell, Thomas E.

2008-01-01

Core body temperature (Tb) is influenced by many physiological factors, including behavioral state, locomotor activity, and biological rhythms. To determine the relative roles of these factors, we examined Tb in orexin knockout (KO) mice, which have a narcolepsy-like phenotype with severe sleep-wake fragmentation. Because orexin is thought to promote heat production during wakefulness, we hypothesized that orexin KO mice would have lower Tb while awake. Surprisingly, the Tb of orexin KO mice was 0.4°C higher than wild-type (WT) littermates during the dark period. Orexin KO mice had normal diurnal variations in Tb, but the ultradian rhythms of Tb, locomotor activity, and wakefulness were markedly reduced. During sustained wakefulness, Tb was the same in both groups. During the first 15 min of spontaneous sleep, the Tb of WT mice decreased by 1.0°C, but Tb in orexin KO mice decreased only 0.4°C. Even during intense recovery sleep after 8 hr of sleep deprivation, the Tb of orexin KO mice remained 0.7°C higher than in WT mice. This blunted fall in Tb during sleep may be due to inadequate activation of heat loss mechanisms or sustained activity in heat-generating systems. These observations reveal an unexpected role for orexin in thermoregulation. In addition, because heat loss is an essential aspect of sleep, the blunted fall in Tb of orexin KO mice may provide an explanation for the fragmented sleep of narcolepsy. PMID:16556901

Toward a Generation Free of Tuberculosis: TB Disease and Infection in Individuals of College Age in the United States

ERIC Educational Resources Information Center

Shah, N. S.; Flood-Bryzman, A.; Jeffries, C.; Scott, J.

2018-01-01

Objectives: To assess the magnitude of active TB disease and latent TB infection (LTBI) in young adults of college age. Participants: Individuals who were aged 18-24 years in 2011 were used as a proxy for college students. Methods: Active TB cases reported to the 2011 US National TB Surveillance System (NTSS) were included. LTBI prevalence was…

Resurrecting social infrastructure as a determinant of urban tuberculosis control in Delhi, India

PubMed Central

2014-01-01

Background The key to universal coverage in tuberculosis (TB) management lies in community participation and empowerment of the population. Social infrastructure development generates social capital and addresses the crucial social determinants of TB, thereby improving program performance. Recently, there has been renewed interest in the concept of social infrastructure development for TB control in developing countries. This study aims to revive this concept and highlight the fact that documentation on ways to operationalize urban TB control is required from a holistic development perspective. Further, it explains how development of social infrastructure impacts health and development outcomes, especially with respect to TB in urban settings. Methods A wide range of published Government records pertaining to social development parameters and TB program surveillance, between 2001 and 2011 in Delhi, were studied. Social infrastructure development parameters like human development index along with other indicators reflecting patient profile and habitation in urban settings were selected as social determinants of TB. These include adult literacy rates, per capita income, net migration rates, percentage growth in slum population, and percentage of urban population living in one-room dwelling units. The impact of the Revised National Tuberculosis Control Program on TB incidence was assessed as an annual decline in new TB cases notified under the program. Univariate linear regression was employed to examine the interrelationship between social development parameters and TB program outcomes. Results The decade saw a significant growth in most of the social development parameters in the State. TB program performance showed 46% increment in lives saved among all types of TB cases per 100,000 population. The 7% reduction in new TB case notifications from the year 2001 to 2011, translates to a logarithmic decline of 5.4 new TB cases per 100,000 population. Except per capita income, literacy, and net migration rates, other social determinants showed significant correlation with decline in new TB cases per 100,000 population. Conclusions Social infrastructure development leads to social capital generation which engenders positive growth in TB program outcomes. Strategies which promote social infrastructure development should find adequate weightage in the overall policy framework for urban TB control in developing countries. PMID:24438431

Resurrecting social infrastructure as a determinant of urban tuberculosis control in Delhi, India.

PubMed

Chandra, Shivani; Sharma, Nandini; Joshi, Kulanand; Aggarwal, Nishi; Kannan, Anjur Tupil

2014-01-17

The key to universal coverage in tuberculosis (TB) management lies in community participation and empowerment of the population. Social infrastructure development generates social capital and addresses the crucial social determinants of TB, thereby improving program performance. Recently, there has been renewed interest in the concept of social infrastructure development for TB control in developing countries. This study aims to revive this concept and highlight the fact that documentation on ways to operationalize urban TB control is required from a holistic development perspective. Further, it explains how development of social infrastructure impacts health and development outcomes, especially with respect to TB in urban settings. A wide range of published Government records pertaining to social development parameters and TB program surveillance, between 2001 and 2011 in Delhi, were studied. Social infrastructure development parameters like human development index along with other indicators reflecting patient profile and habitation in urban settings were selected as social determinants of TB. These include adult literacy rates, per capita income, net migration rates, percentage growth in slum population, and percentage of urban population living in one-room dwelling units. The impact of the Revised National Tuberculosis Control Program on TB incidence was assessed as an annual decline in new TB cases notified under the program. Univariate linear regression was employed to examine the interrelationship between social development parameters and TB program outcomes. The decade saw a significant growth in most of the social development parameters in the State. TB program performance showed 46% increment in lives saved among all types of TB cases per 100,000 population. The 7% reduction in new TB case notifications from the year 2001 to 2011, translates to a logarithmic decline of 5.4 new TB cases per 100,000 population. Except per capita income, literacy, and net migration rates, other social determinants showed significant correlation with decline in new TB cases per 100,000 population. Social infrastructure development leads to social capital generation which engenders positive growth in TB program outcomes. Strategies which promote social infrastructure development should find adequate weightage in the overall policy framework for urban TB control in developing countries.

Scaling up of HIV-TB collaborative activities: Achievements and challenges in India.

PubMed

Deshmukh, Rajesh; Shah, Amar; Sachdeva, K S; Sreenivas, A N; Gupta, R S; Khaparde, S D

2016-01-01

India has been implementing HIV/TB collaborative activities since 2001 with rapid scale-up of infrastructure across the country during past decade in National AIDS Control Programme and Revised National TB Control Programme. India has shown over 50% reduction in new infections and around 35% reduction in AIDS-related deaths, thereby being one of the success stories globally. Substantial progress in the implementation of collaborative TB/HIV activities has occurred in India and it is marching towards target set out in the Global Plan to Stop TB and endorsed by the UN General Assembly to halve HIV associated TB deaths by 2015. While the successful approaches have led to impressive gains in HIV/TB control in India, there are emerging challenges including newer pockets with rising HIV trends in North India, increasing drug resistance, high mortality among co-infected patients, low HIV testing rates among TB patients in northern and eastern states in India, treatment delays and drop-outs, stigma and discrimination, etc. In spite of these difficulties, established HIV/TB coordination mechanisms at different levels, rapid scale-up of facilities with decentralisation of treatment services, regular joint supervision and monitoring, newer initiatives like use of rapid diagnostics for early diagnosis of TB among people living with HIV, TB notification, etc. have led to success in combating the threat of HIV/TB in India. This article highlights the steps taken by India, one of the largest HIV/TB programmes in world, in scaling up of the joint HIV-TB collaborative activities, the achievements so far and discusses the emerging challenges which could provide important lessons for other countries in scaling up their programmes. Copyright © 2016 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

Hierarchy Low CD4+/CD8+ T-Cell Counts and IFN-γ Responses in HIV-1+ Individuals Correlate with Active TB and/or M.tb Co-Infection.

PubMed

Shao, Lingyun; Zhang, Xinyun; Gao, Yan; Xu, Yunya; Zhang, Shu; Yu, Shenglei; Weng, Xinhua; Shen, Hongbo; Chen, Zheng W; Jiang, Weimin; Zhang, Wenhong

2016-01-01

Detailed studies of correlation between HIV-M.tb co-infection and hierarchy declines of CD8+/CD4+ T-cell counts and IFN-γ responses have not been done. We conducted case-control studies to address this issue. 164 HIV-1-infected individuals comprised of HIV-1+ATB, HIV-1+LTB and HIV-1+TB- groups were evaluated. Immune phenotyping and complete blood count (CBC) were employed to measure CD4+ and CD8+ T-cell counts; T.SPOT.TB and intracellular cytokine staining (ICS) were utilized to detect ESAT6, CFP10 or PPD-specific IFN-γ responses. There were significant differences in median CD4+ T-cell counts between HIV-1+ATB (164/μL), HIV-1+LTB (447/μL) and HIV-1+TB- (329/μL) groups. Hierarchy low CD4+ T-cell counts (<200/μL, 200-500/μL, >500/μL) were correlated significantly with active TB but not M.tb co-infection. Interestingly, hierarchy low CD8+ T-cell counts were not only associated significantly with active TB but also with M.tb co-infection (P<0.001). Immunologically, HIV-1+ATB group showed significantly lower numbers of ESAT-6-/CFP-10-specific IFN-γ+ T cells than HIV-1+LTB group. Consistently, PPD-specific IFN-γ+CD4+/CD8+ T effector cells in HIV-1+ATB group were significantly lower than those in HIV-1+LTB group (P<0.001). Hierarchy low CD8+ T-cell counts and effector function in HIV-1-infected individuals are correlated with both M.tb co-infection and active TB. Hierarchy low CD4+ T-cell counts and Th1 effector function in HIV-1+ individuals are associated with increased frequencies of active TB, but not M.tb co-infection.

Tuberculosis Incidence and Risk Factors Among Human Immunodeficiency Virus (HIV)-Infected Adults Receiving Antiretroviral Therapy in a Large HIV Program in Nigeria

PubMed Central

Chang, Charlotte A.; Meloni, Seema Thakore; Eisen, Geoffrey; Chaplin, Beth; Akande, Patrick; Okonkwo, Prosper; Rawizza, Holly E.; Tchetgen Tchetgen, Eric; Kanki, Phyllis J.

2015-01-01

Background. Despite the benefits of antiretroviral therapy (ART), tuberculosis (TB) is the leading cause of mortality among human immunodeficiency virus (HIV)-infected persons in Africa. Nigeria bears the highest TB burden in Africa and second highest HIV burden globally. This long-term multicenter study aimed to determine the incidence rate and predictors of TB in adults in the Harvard/AIDS Prevention Initiative in Nigeria (APIN) and President's Emergency Plan for AIDS Relief (PEPFAR) Nigeria ART program. Methods. This retrospective evaluation used data collected from 2004 to 2012 through the Harvard/APIN PEPFAR program. Risk factors for incident TB were determined using multivariate Cox proportional hazards regression with time-dependent covariates. Results. Of 50 320 adults enrolled from 2005 to 2010, 11 092 (22%) had laboratory-confirmed active TB disease at ART initiation, and 2021 (4%) developed active TB after commencing ART. During 78 228 total person-years (PY) of follow-up, the TB incidence rate was 25.8 cases per 1000 PY (95% confidence interval [CI], 24.7–27.0) overall, and it decreased significantly both with duration on ART and calendar year. Risk factors at ART initiation for incident TB included the following: earlier ART enrollment year, tenofovir-containing initial ART regimen, and World Health Organization clinical stage above 1. Time-updated risk factors included the following: low body mass index, low CD4+ cell count, unsuppressed viral load, anemia, and ART adherence below 80%. Conclusions. The rate of incident TB decreased with longer duration on ART and over the program years. The strongest TB risk factors were time-updated clinical markers, reinforcing the importance of consistent clinical and laboratory monitoring of ART patients in prompt diagnosis and treatment of TB and other coinfections. PMID:26613097

Rationale and design of a randomized controlled trial of the effect of retinol and vitamin D supplementation on treatment in active pulmonary tuberculosis patients with diabetes

PubMed Central

2013-01-01

Background The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas β-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients. Methods/design This is a 2×2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti-tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L. Discussion This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM. Trial registration ChiCTR-TRC-12002546 PMID:23442225

Rationale and design of a randomized controlled trial of the effect of retinol and vitamin D supplementation on treatment in active pulmonary tuberculosis patients with diabetes.

PubMed

Wang, Qiuzhen; Ma, Aiguo; Bygbjerg, Ib Christian; Han, Xiuxia; Liu, Yufeng; Zhao, Shanliang; Cai, Jing

2013-02-26

The association between pulmonary tuberculosis (PTB) and diabetes mellitus (DM) has been previously attracted much attention. Diabetes alters immunity to tuberculosis, leading to more frequent treatment failure in TB patients with DM. Moreover, TB and DM often coincide with micronutrients deficiencies, such as retinol and vitamin D, which are especially important to immunity of the body and may influence pancreas β-cell function. However, the effects of retinol and vitamin D supplementation in active TB patients with diabetes on treatment outcomes, immune and nutrition state are still uncertain. We are conducting a randomized controlled trial of vitamin A and/or D in active PTB patients with DM in a network of 4 TB treatment clinics to determine whether the supplementation could improve the outcome in the patients. This is a 2×2 factorial trial. We plan to enroll 400 active PTB patients with DM, and randomize them to VA (2000 IU daily retinol); VD (400 IU daily cholecalciferol); VAD (2000 IU daily retinol plus 400 IU cholecalciferol) or control (placebo) group. Our primary outcome measure is the efficacy of anti-tuberculosis treatment and ameliorating of glucose metabolism, and the secondary outcome measure being immune and nutrition status of the subjects. Of the first 37 subjects enrolled: 8 have been randomized to VA, 10 to VD, 9 to VAD and 10 to control. To date, the sample is 97.3% Han Chinese and 91.9% female. The average fasting plasma glucose level is 12.19 mmol/L. This paper describes the design and rationale of a randomized clinical trial comparing VA and/or VD supplementation to active pulmonary TB patients with DM. Our trial will allow rigorous evaluation of the efficacy of the supplementation to active TB and DM therapy for improving clinical outcomes and immunological condition. This detailed description of trial methodology can serve as a template for the development of future treatment scheme for active TB patient with DM. ChiCTR-TRC-12002546.

Major Challenges in Clinical Management of TB/HIV Coinfected Patients in Eastern Europe Compared with Western Europe and Latin America

PubMed Central

Efsen, Anne Marie W.; Schultze, Anna; Post, Frank A.; Panteleev, Alexander; Furrer, Hansjakob; Miller, Robert F.; Losso, Marcelo H.; Toibaro, Javier; Skrahin, Aliaksandr; Miro, Jose M.; Caylà, Joan A.; Girardi, Enrico; Bruyand, Mathias; Obel, Niels; Podlekareva, Daria N.; Lundgren, Jens D.; Mocroft, Amanda; Kirk, Ole

2015-01-01

Objectives Rates of TB/HIV coinfection and multi-drug resistant (MDR)-TB are increasing in Eastern Europe (EE). We aimed to study clinical characteristics, factors associated with MDR-TB and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients in EE, Western Europe (WE) and Latin America (LA). Design and Methods Between January 1, 2011, and December 31, 2013, 1413 TB/HIV patients (62 clinics in 19 countries in EE, WE, Southern Europe (SE), and LA) were enrolled. Results Significant differences were observed between EE (N = 844), WE (N = 152), SE (N = 164), and LA (N = 253) in the proportion of patients with a definite TB diagnosis (47%, 71%, 72% and 40%, p<0.0001), MDR-TB (40%, 5%, 3% and 15%, p<0.0001), and use of combination antiretroviral therapy (cART) (17%, 40%, 44% and 35%, p<0.0001). Injecting drug use (adjusted OR (aOR) = 2.03 (95% CI 1.00–4.09), prior anti-TB treatment (3.42 (1.88–6.22)), and living in EE (7.19 (3.28–15.78)) were associated with MDR-TB. Among 585 patients with drug susceptibility test (DST) results, the empiric (i.e. without knowledge of the DST results) anti-TB treatment included ≥3 active drugs in 66% of participants in EE compared with 90–96% in other regions (p<0.0001). Conclusions In EE, TB/HIV patients were less likely to receive a definite TB diagnosis, more likely to house MDR-TB and commonly received empiric anti-TB treatment with reduced activity. Improved management of TB/HIV patients in EE requires better access to TB diagnostics including DSTs, empiric anti-TB therapy directed at both susceptible and MDR-TB, and more widespread use of cART. PMID:26716686

Inhibition of the ERK phosphorylation plays a role in terbinafine-induced p21 up-regulation and DNA synthesis inhibition in human vascular endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ho, P.-Y.; Hsu, S.-P.; Liang, Y.-C.

2008-05-15

Previously, we showed that terbinafine (TB) induces cell-cycle arrest in cultured human umbilical vein endothelial cells (HUVEC) through an up-regulation of the p21 protein. The aim of this study is to delineate the molecular mechanisms underlying TB-induced increase of p21 protein. RT-PCR analysis demonstrated that the mRNA levels of p21 and p53 were increased in the TB-treated HUVEC. The p21 promoter activity was also increased by TB treatment. Transfection of HUVEC with p53 dominant negative (DN) abolished the TB-induced increases of p21 promoter activity and protein level, suggesting that the TB-induced increase of p21 is p53-dependent. Western blot analysis demonstratedmore » that TB decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK). Over-expression of mitogen-activated protein kinase (MEK)-1, the immediate upstream activator kinase of ERK, abolished the TB-induced increases of p21 and p53 protein and decrease of thymidine incorporation. The ERK inhibitor (PD98059) enhanced the TB-induced inhibition of thymidine incorporation into HUVEC. Taken together, these data suggest that the decrease of ERK activity plays a role in the TB-induced up-regulation of p21 in HUVEC. On the other hand, pretreatment of the cells with geranylgeraniol (GGOH), farnesol (FOH), or Ras inhibitor peptide did not affect the TB-induced decrease of thymidine incorporation. Taken together, our results suggest that TB might cause a decrease of MEK, which in turn up-regulates p53 through the inhibition of ERK phosphorylation, and finally causes an increase of p21 expression and cell-cycle arrest.« less

Differential expression of antimicrobial peptides in active and latent tuberculosis and its relationship with diabetes mellitus.

PubMed

Gonzalez-Curiel, Irma; Castañeda-Delgado, Julio; Lopez-Lopez, Nallely; Araujo, Zaida; Hernandez-Pando, Rogelio; Gandara-Jasso, Benjamin; Macias-Segura, Noe; Enciso-Moreno, Antonio; Rivas-Santiago, Bruno

2011-08-01

Tuberculosis (TB) is one of the most important infectious diseases, causing 1.8 million deaths annually worldwide. This problem has increased because of the association with human immmunodeficiency virus and diabetes mellitus type 2, mainly in developing countries. In the past few years it has been highlighted the significance of antimicrobial peptides in the immunopathogenesis of TB ex vivo and in experimental models studies. In this study we analyzed the expression of CAMP, DEFA1, DEFB4, and DEFB103A in patients with latent TB and progressive TB with and without comorbidity with diabetes mellitus type 2. Antimicrobial peptide gene expression increased during progressive TB, which could be used as a biomarker for reactivation. By contrast, patients with diabetes mellitus type 2 have lower antimicrobial peptides gene expression, suggesting that the lack of its proper production in these patients contribute to enhance the risk for TB reactivation. Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Undernutrition & tuberculosis in India: Situation analysis & the way forward

PubMed Central

Padmapriyadarsini, C.; Shobana, M.; Lakshmi, M.; Beena, T.; Swaminathan, Soumya

2016-01-01

Undernutrition and tuberculosis (TB) are linked and have a bidirectional relationship. Undernutrition increases the risk of TB which in turn, can lead to malnutrition. Undernutrition not only is a risk factor for progression of latent TB infection to active disease, but also increases the risk of drug toxicity, relapse and death once TB develops. The dietary intake of TB patients in the country is inadequate. Nutritional supplementation in patients with TB is associated with faster sputum conversion, higher cure and treatment completion rates, significant gain in body weight and body composition as well as better performance status. The Government of India has various social support schemes (including nutrition supplementation schemes) and policies, at the Centre as well as State levels. Here we discuss some successful examples and suggest a few solutions to address this gap; like considering TB patients as a vulnerable group for “Targeted Public Distribution System” and providing extra rations for the duration of treatment. Recommendations for the research community, civil societies, government organizations, non-governmental and corporate sector on the actions needed to achieve the goals of the End TB Strategy are also provided. Ultimately, reduction of TB burden in India and its elimination will require improving the nutritional status of the community as a whole. PMID:27834321

[Active tuberculosis in a cohort of HIV-infected inmates in a prison in Mexico City: clinical and epidemiological characteristics].

PubMed

Hernández-León, Christian; Badial-Hernández, Florentino; Ponce-de-León, Alfredo; Sierra-Madero, Juan G; Martínez-Gamboa, Areli; Crabtree-Ramírez, Brenda; Bautista-Arredondo, Sergio; González-Aguirre, Adrián; Guerrero-Almeida, María de Lourdes; del Valle, J Miriam Bobadilla; González-Rodríguez, Andrea; Sifuentes-Osornio, José

2012-01-01

To determine the clinical and epidemiological characteristics of prison inmates with active tuberculosis in HIV-positive prison populations. We conducted a cohort study in HIV-infected subjects in a prison in Mexico City, with the aim of determining clinical and epidemiological characteristics of cases with active TB. We detected 172 HIV infected inmates and TB in 28 of them (16.3%) - 21 (12.2) with pulmonary TB--with an incidence rate of 7.7/100 persons/year for active TB and 4.7/100 persons/year for pulmonary TB. No drug resistance was found. Two clusters (4 and 2 subjects) were observed after RFLP-typing of 18 isolates, with a transmission rate of 11% by molecular and clinical analysis. The prevalence of active TB was found to be a thousand times greater than in the general population. Evidence of transmission inside the prison was also found.

Miliary tuberculosis: a severe opportunistic infection in juvenile systemic lupus erythematosus patients.

PubMed

Freire, Priscilla S; Montoni, João D; Ribeiro, Aline S M; Marques, Heloísa H; Mauad, Thais; Silva, Clovis A

2016-01-01

One of the main issues in juvenile systemic lupus erythematosus (JSLE) patients is infection, such as tuberculosis (TB). Of note, SLE patients are susceptible to pulmonary and extrapulmonary TB. However, to our knowledge, this contagious disease was rarely reported in pediatric lupus population, particularly diffuse or miliary TB. Therefore, from January 1983 to December 2011, 5,635 patients were followed-up at our Pediatric Rheumatology Unit and 285 (5%) of them met the American College of Rheumatology classification criteria for SLE. Four (1.4%) of our JSLE patients had disseminated TB and were described herein. All of them were female gender, received BCG vaccination and did not have a history of TB household contact. The median of current age at TB diagnosis and the period between JSLE and TB diagnosis were 17 years old (range 14-20) and 5.5 years (range 2-7), respectively. All patients developed miliary TB during the course of the disease. The median of SLE Disease Activity Index 2000 (SLEDAI-2K) was 4 (2-16) and the patients were treated with immunosuppressive agents (glucocorticoid, azathioprine and/or intravenous cyclophosphamide). Two of them presented sepsis and TB diagnosis was only established at autopsy, especially with lungs, central nervous system and abdominal involvements. Anti-TB therapy (isoniazid, rifampicin and pyrazinamide) was indicated in the other two TB cases, however they deceased. Miliary TB is a rare and severe opportunist infection in pediatric lupus population. This study reinforces the importance of routine searches for TB in JSLE patients. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

[Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (i): Epidemiology and diagnosis. Congenital tuberculosis].

PubMed

Baquero-Artigao, F; Mellado Peña, M J; Del Rosal Rabes, T; Noguera Julián, A; Goncé Mellgren, A; de la Calle Fernández-Miranda, M; Navarro Gómez, M L

2015-10-01

Tuberculosis (TB) screening in pregnancy using tuberculin skin test (TST) is recommended in case of symptoms of TB disease, close contact with a patient with infectious TB, or high risk of developing active disease. The new interferon gamma release assay (IGRA) tests are recommended in BCG-vaccinated pregnant women with positive TST and no known risk factors for TB, and in those immunocompromised, with clinical suspicion of TB but negative TST. TB diagnosis is difficult due to the non-specific symptoms, the increased frequency of extrapulmonary disease, the delay in radiological examinations, and the high rate of tuberculin anergy. Neonatal TB can be acquired in utero (congenital TB), or through airborne transmission after delivery (postnatal TB). Congenital TB is extremely rare and does not cause fetal malformations. It may be evident at birth, although it usually presents after the second week of life. In newborns with no family history of TB, the disease should be considered in cases of miliary pneumonia, hepatosplenomegaly with focal lesions, or lymphocytic meningitis with hypoglycorrhachia, especially in those born to immigrants from high TB-burden countries. TST is usually negative, and IGRAs have lower sensitivity than in older children. However, the yield of acid-fast smear and culture is higher, mostly in congenital TB. Molecular diagnosis techniques enable early diagnosis and detection of drug resistance mutations. There is a substantial risk of disseminated disease and death. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Toward a generation free of tuberculosis: TB disease and infection in individuals of college age in the United States.

PubMed

Shah, N S; Flood-Bryzman, A; Jeffries, C; Scott, J

2018-01-01

To assess the magnitude of active TB disease and latent TB infection (LTBI) in young adults of college age. Individuals who were aged 18-24 years in 2011 were used as a proxy for college students. Active TB cases reported to the 2011 US National TB Surveillance System (NTSS) were included. LTBI prevalence was calculated from the 2011-2012 National Health and Nutrition Examination Survey. The 2011 American Community Survey was used to calculate population denominators. Analyses were stratified by nativity. Active TB disease incidence among persons aged 18-24 years was 2.82/100,000, 18.8/100,000 among foreign-born individuals and 0.9/100,000 among US-born individuals. In 2011, 878 TB cases were reported; 629 (71.6%) were foreign-born. LTBI prevalence among persons of 18-24 years was 2.5%: 8.7% and 1.3% among foreign-born and US-born, respectively. Active screening and treatment programs for foreign-born young adults could identify TB cases earlier and provide an opportunity for prevention efforts.

Predicting tuberculosis risk in the foreign-born population of British Columbia, Canada: study protocol for a retrospective population-based cohort study.

PubMed

Ronald, Lisa A; Campbell, Jonathon R; Balshaw, Robert F; Roth, David Z; Romanowski, Kamila; Marra, Fawziah; Cook, Victoria J; Johnston, James C

2016-11-25

Improved understanding of risk factors for developing active tuberculosis (TB) will better inform decisions about diagnostic testing and treatment for latent TB infection (LTBI) in migrant populations in low-incidence regions. We aim to examine TB risk factors among the foreign-born population in British Columbia (BC), Canada, and to create and validate a clinically relevant multivariate risk score to predict active TB. This retrospective population-based cohort study will include all foreign-born individuals who acquired permanent resident status in Canada between 1 January 1985 and 31 December 2013 and acquired healthcare coverage in BC at any point during this period. Multiple administrative databases and disease registries will be linked, including a National Immigration Database, BC Provincial Health Insurance Registration, physician billings, hospitalisations, drugs dispensed from community pharmacies, vital statistics, HIV testing and notifications, cancer, chronic kidney disease and dialysis treatment, and all TB and LTBI testing and treatment data in BC. Extended proportional hazards regression will be used to estimate risk factors for TB and to create a prognostic TB risk score. Ethical approval for this study has been obtained from the University of British Columbia Clinical Ethics Review Board. Once completed, study findings will be presented at conferences and published in peer-reviewed journals. An online TB risk score calculator will also be created. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Pulmonary and latent tuberculosis screening in opiate drug users: an essential and neglected approach for harm-reduction facilities.

PubMed

Honarvar, Behnam; Lankarani, Kamran Bagheri; Odoomi, Neda; Roudgari, Amir; Moghadami, Mohsen; Kazerooni, Parvin Afsar; Abadi, Alireza Hassan

2013-01-01

Opiates drug users are at much higher risk of developing tuberculosis (TB) infection than general population. We conducted this study to determine the susceptibility for pulmonary and latent TB infection in opiates drug users. In this cross-sectional study, all opiates drug users referred to drop-in centers, methadone maintenance clinics, and harm-reduction facilities affiliated with Shiraz University of Medical Sciences in southern Iran were screened for pulmonary and latent TB infection. The participation rate of opiate drug users was 87.66% (263 of 300). Mean age was 37.37 ± 8.33 (range, 20-65) years. Two hundred twenty-six (85.93%) were male and 197 (74.90%) were injection drug users (IDUs). One hundred sixty-three (61.97%) had TB-related symptoms. Culture for TB was positive in 3 patients (1.14%) (2 non-IDUs and 1 IDU). Two patients (0.76%) showed acid-fast bacilli in the direct sputum smear. Eighty-five of 244 patients (34.83%) had a 5- to 10-mm induration in the skin TB test. Twenty-nine of 223 patients (13%) had abnormal findings from chest x-ray films. The prevalence of smear-positive pulmonary TB in opiate drug users is more than 100 times in the general population in Iran. Therefore, active and appropriate screening to detect pulmonary TB infection should be integrated into routine activities at all harm-reduction facilities for drug users, irrespective of their route of drug use or human immunodeficiency virus status, in this country.

Extension of the energy range of the experimental activation cross-sections data of longer-lived products of proton induced nuclear reactions on dysprosium up to 65MeV.

PubMed

Tárkányi, F; Ditrói, F; Takács, S; Hermanne, A; Ignatyuk, A V

2015-04-01

Activation cross-sections data of longer-lived products of proton induced nuclear reactions on dysprosium were extended up to 65MeV by using stacked foil irradiation and gamma spectrometry experimental methods. Experimental cross-sections data for the formation of the radionuclides (159)Dy, (157)Dy, (155)Dy, (161)Tb, (160)Tb, (156)Tb, (155)Tb, (154m2)Tb, (154m1)Tb, (154g)Tb, (153)Tb, (152)Tb and (151)Tb are reported in the 36-65MeV energy range, and compared with an old dataset from 1964. The experimental data were also compared with the results of cross section calculations of the ALICE and EMPIRE nuclear model codes and of the TALYS nuclear reaction model code as listed in the latest on-line libraries TENDL 2013. Copyright © 2015. Published by Elsevier Ltd.

The epidemiology of tuberculosis in health care workers in South Africa: a systematic review.

PubMed

Grobler, Liesl; Mehtar, Shaheen; Dheda, Keertan; Adams, Shahieda; Babatunde, Sanni; van der Walt, Martie; Osman, Muhammad

2016-08-20

In South Africa, workplace acquired tuberculosis (TB) is a significant occupational problem among health care workers. In order to manage the problem effectively it is important to know the burden of TB in health care workers. This systematic review describes the epidemiology of TB in South African health care workers. A comprehensive search of electronic databases [MEDLINE, EMBASE, Web of Science (Social Sciences Citation Index/Science Citation Index), Cochrane Library (including CENTRAL register of Controlled Trials), CINAHL and WHO International Clinical Trials Registry Platform (ICTRP)] was conducted up to April 2015 for studies reporting on any aspect of TB epidemiology in health care workers in South Africa. Of the 16 studies included in the review, ten studies reported on incidence of active TB disease in health care workers, two report on the prevalence of active TB disease, two report on the incidence of latent TB infection, three report on the prevalence of latent TB infection and four studies report on the number of TB cases in health care workers in various health care facilities in South Africa. Five studies provide information on risk factors for TB in health care workers. All of the included studies were conducted in publicly funded health care facilities; predominately located in KwaZulu-Natal and Western Cape provinces. The majority of the studies reflect a higher incidence and prevalence of active TB disease in health care workers, including drug-resistant TB, compared to the surrounding community or general population. There is relatively little research on the epidemiology of TB in health care workers in South Africa, despite the importance of the issue. To determine the true extent of the TB epidemic in health care workers, regular screening for TB disease should be conducted on all health care workers in all health care facilities, but future research is required to investigate the optimal approach to TB screening in health care workers in South Africa. The evidence base shows a high burden of both active and latent TB in health care workers in South Africa necessitating an urgent need to improve existing TB infection, prevention and control measures in South African health care facilities.

Evaluation of a tuberculosis active case finding project in peri-urban areas, Myanmar: 2014-2016.

PubMed

Aye, Sandar; Majumdar, Suman S; Oo, Myo Minn; Tripathy, Jaya Prasad; Satyanarayana, S; Kyaw, Nang Thu Thu; Kyaw, Khine Wut Yee; Oo, Nay Lynn; Thein, Saw; Thu, Myat Kyaw; Soe, Kyaw Thu; Aung, Si Thu

2018-05-01

We assessed the effect of an active case finding (ACF) project on tuberculosis (TB) case notification and the yields from a household and neigbourhood intervention (screening contacts of historical index TB patients diagnosed >24months ago) and a community intervention (screening attendants of health education sessions/mobile clinics). Cross-sectional analysis of project records, township TB registers and annual TB reports. In the household and neigbourhood intervention, of 56,709 people screened, 1,076 were presumptive TB and 74 patients were treated for active TB with a screening yield of 0.1% and a yield from presumptive cases of 6.9%. In the community intervention, of 162,881 people screened, 4,497 were presumptive TB and 984 were treated for active TB with a screening yield of 0.6% and yield from presumptive cases of 21.9%. Of active TB cases, 94% were new, 89% were pulmonary, 44% were bacteriologically-confirmed and 5% had HIV. Case notification rates per 100,000 in project townships increased from 142 during baseline (2011-2013) to 148 during intervention (2014-2016) periods. The yield from household and neigbourhood intervention was lower than community intervention. This finding highlights reconsidering the strategy of screening of contacts from historical index cases. Strategies to reach high-risk groups should be explored for future ACF interventions to increase yield of TB. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Nitroimidazoles for the treatment of TB: past, present and future

PubMed Central

Mukherjee, Tathagata; Boshoff, Helena

2011-01-01

Tuberculosis remains a leading cause of death resulting from an infectious agent, and the spread of multi- and extensively drug-resistant strains of Mycobacterium tuberculosis poses a threat to management of global health. New drugs that effectively shorten the duration of treatment and are active against drug-resistant strains of this pathogen are urgently required to develop effective chemotherapies to combat this disease. Two nitroimidazoles, PA-824 and OPC-67683, are currently in Phase II clinical trials for the treatment of TB and the outcome of these may determine the future directions of drug development for anti-tubercular nitroimidazoles. In this review we summarize the development of these nitroimidazoles and alternative analogs in these series that may offer attractive alternatives to PA-824 and OPC-67683 for further development in the drug-discovery pipeline. Lastly, the potential pitfalls in the development of nitroimidazoles as drugs for TB are discussed. PMID:21879846

Analysis of Host Responses to Mycobacterium tuberculosis Antigens in a Multi-Site Study of Subjects with Different TB and HIV Infection States in Sub-Saharan Africa

PubMed Central

Sutherland, Jayne S.; Lalor, Maeve K.; Black, Gillian F.; Ambrose, Lyn R.; Loxton, Andre G.; Chegou, Novel N.; Kassa, Desta; Mihret, Adane; Howe, Rawleigh; Mayanja-Kizza, Harriet; Gomez, Marie P.; Donkor, Simon; Franken, Kees; Hanekom, Willem; Klein, Michel R.; Parida, Shreemanta K.; Boom, W. Henry; Thiel, Bonnie A.; Crampin, Amelia C.; Ota, Martin; Walzl, Gerhard; Ottenhoff, Tom H. M.; Dockrell, Hazel M.; Kaufmann, Stefan H. E.

2013-01-01

Background Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas. Methods We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens. Results There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST- and TST+ contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST+ contacts (LTBI) compared to TB and TST- contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen. Conclusions Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials. PMID:24040170

Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa.

PubMed

Sutherland, Jayne S; Lalor, Maeve K; Black, Gillian F; Ambrose, Lyn R; Loxton, Andre G; Chegou, Novel N; Kassa, Desta; Mihret, Adane; Howe, Rawleigh; Mayanja-Kizza, Harriet; Gomez, Marie P; Donkor, Simon; Franken, Kees; Hanekom, Willem; Klein, Michel R; Parida, Shreemanta K; Boom, W Henry; Thiel, Bonnie A; Crampin, Amelia C; Ota, Martin; Walzl, Gerhard; Ottenhoff, Tom H M; Dockrell, Hazel M; Kaufmann, Stefan H E

2013-01-01

Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas. We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens. There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen. Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials.

Tuberculosis infection among homeless persons and caregivers in a high-tuberculosis-prevalence area in Japan: a cross-sectional study

PubMed Central

2011-01-01

Background Tuberculosis (TB) is a major public health problem. The Airin district of Osaka City has a large population of homeless persons and caregivers and is estimated to be the largest TB-endemic area in the intermediate-prevalence country, Japan. However, there have been few studies of homeless persons and caregivers. The objective of this study is to detect active TB and to assess the prevalence and risk factors for latent TB infection among homeless persons and caregivers. Methods We conducted a cross-sectional study for screening TB infection (active and latent TB infections) using questionnaire, chest X-ray (CXR), newly available assay for latent TB infection (QuantiFERON-TB Gold In-Tube; QFT) and clinical evaluation by physicians at the Osaka Socio-Medical Center Hospital between July 2007 and March 2008. Homeless persons and caregivers, aged 30-74 years old, who had not received CXR examination within one year, were recruited. As for risk factors of latent TB infection, the odds ratios (OR) and 95% confidence intervals (95% CI) for QFT-positivity were calculated using logistic regression model. Results Complete responses were available from 436 individuals (263 homeless persons and 173 caregivers). Four active TB cases (1.5%) among homeless persons were found, while there were no cases among caregivers. Out of these four, three had positive QFT results. One hundred and thirty-three (50.6%) homeless persons and 42 (24.3%) caregivers had positive QFT results. In multivariate analysis, QFT-positivity was independently associated with a long time spent in the Airin district: ≥10 years versus <10 years for homeless (OR = 2.53; 95% CI, 1.39-4.61) and for caregivers (OR = 2.32; 95% CI, 1.05-5.13), and the past exposure to TB patients for caregivers (OR = 3.21; 95% CI, 1.30-7.91) but not for homeless persons (OR = 1.51; 95% CI, 0.71-3.21). Conclusions Although no active TB was found for caregivers, one-quarter of them had latent TB infection. In addition to homeless persons, caregivers need examinations for latent TB infection as well as active TB and careful follow-up, especially when they have spent a long time in a TB-endemic area and/or have been exposed to TB patients. PMID:21255421

Mycobacteria-specific cytokine responses as correlates of treatment response in active and latent tuberculosis.

PubMed

Clifford, Vanessa; Tebruegge, Marc; Zufferey, Christel; Germano, Susie; Forbes, Ben; Cosentino, Lucy; McBryde, Emma; Eisen, Damon; Robins-Browne, Roy; Street, Alan; Denholm, Justin; Curtis, Nigel

2017-08-01

A biomarker indicating successful tuberculosis (TB) therapy would assist in determining appropriate length of treatment. This study aimed to determine changes in mycobacteria-specific antigen-induced cytokine biomarkers in patients receiving therapy for latent or active TB, to identify biomarkers potentially correlating with treatment success. A total of 33 adults with active TB and 36 with latent TB were followed longitudinally over therapy. Whole blood stimulation assays using mycobacteria-specific antigens (CFP-10, ESAT-6, PPD) were done on samples obtained at 0, 1, 3, 6 and 9 months. Cytokine responses (IFN-γ, IL-1ra, IL-2, IL-10, IL-13, IP-10, MIP-1β, and TNF-α) in supernatants were measured by Luminex xMAP immunoassay. In active TB cases, median IL-1ra (with CFP-10 and with PPD stimulation), IP-10 (CFP-10, ESAT-6), MIP-1β (ESAT-6, PPD), and TNF-α (ESAT-6) responses declined significantly over the course of therapy. In latent TB cases, median IL-1ra (CFP-10, ESAT-6, PPD), IL-2 (CFP-10, ESAT-6), and IP-10 (CFP-10, ESAT-6) responses declined significantly. Mycobacteria-specific cytokine responses change significantly over the course of therapy, and their kinetics in active TB differ from those observed in latent TB. In particular, mycobacteria-specific IL-1ra responses are potential correlates of successful therapy in both active and latent TB. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

The low-energy β(-) and electron emitter (161)Tb as an alternative to (177)Lu for targeted radionuclide therapy.

PubMed

Lehenberger, Silvia; Barkhausen, Christoph; Cohrs, Susan; Fischer, Eliane; Grünberg, Jürgen; Hohn, Alexander; Köster, Ulli; Schibli, Roger; Türler, Andreas; Zhernosekov, Konstantin

2011-08-01

The low-energy β(-) emitter (161)Tb is very similar to (177)Lu with respect to half-life, beta energy and chemical properties. However, (161)Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to (177)Lu. It also emits low-energy photons that are useful for gamma camera imaging. The (160)Gd(n,γ)(161)Gd→(161)Tb production route was used to produce (161)Tb by neutron irradiation of massive (160)Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) (161)Tb from the bulk of the (160)Gd target and from its stable decay product (161)Dy. (161)Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. (177)Lu. A (161)Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Up to 15 GBq of (161)Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%-90% of the available (161)Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The (161)Tb obtained was of the quality required to prepare (161)Tb-DOTA-Tyr3-octreotate. We were able to produce (161)Tb in n.c.a. form by irradiating highly enriched (160)Gd targets; it can be obtained in the quantity and quality required for the preparation of (161)Tb-labeled therapeutic agents. Copyright © 2011 Elsevier Inc. All rights reserved.

The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets

PubMed Central

Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna

2015-01-01

The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal. PMID:25635061

Active Tuberculosis Case Finding Interventions Among Immigrants, Refugees and Asylum Seekers in Italy

PubMed Central

Schepisi, Monica Sañé; Gualano, Gina; Piselli, Pierluca; Mazza, Marta; D’Angelo, Donatella; Fasciani, Francesca; Barbieri, Alberto; Rocca, Giorgia; Gnolfo, Filippo; Olivani, Piefranco; Ferrarese, Maurizio; Codecasa, Luigi Ruffo; Palmieri, Fabrizio; Girardi, Enrico

2016-01-01

In Italy tuberculosis (TB) is largely concentrated in vulnerable groups such as migrants and in urban settings. We analyzed three TB case finding interventions conducted at primary centers and mobile clinics for regular/irregular immigrants and refugees/asylum seekers performed over a four-year period (November 2009-March 2014) at five different sites in Rome and one site in Milan, Italy. TB history and presence of symptoms suggestive of active TB were investigated by verbal screening through a structured questionnaire in migrants presenting for any medical condition to out-patient and mobile clinics. Individuals reporting TB history or symptoms were referred to a TB clinic for diagnostic workup. Among 6347 migrants enrolled, 891 (14.0%) reported TB history or symptoms suggestive of active TB and 546 (61.3%) were referred to the TB clinic. Of them, 254 (46.5%) did not present for diagnostic evaluation. TB was diagnosed in 11 individuals representing 0.17% of those screened and 3.76% of those evaluated. The overall yield of this intervention was in the range reported for other TB screening programs for migrants, although we recorded an unsatisfactory adherence to diagnostic workup. Possible advantages of this intervention include low cost and reduced burden of medical procedures for the screened population. PMID:27403270

"The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" - Meeting report.

PubMed

Boggiano, Cesar; Eichelberg, Katrin; Ramachandra, Lakshmi; Shea, Jaqueline; Ramakrishnan, Lalita; Behar, Samuel; Ernst, Joel D; Porcelli, Steven A; Maeurer, Markus; Kornfeld, Hardy

2017-06-14

Tuberculosis (TB) is the major cause of death from infectious diseases around the world, particularly in HIV infected individuals. TB vaccine design and development have been focused on improving Bacille Calmette-Guérin (BCG) and evaluating recombinant and viral vector expressed Mycobacterium tuberculosis (Mtb) proteins, for boosting BCG-primed immunity, but these approaches have not yet yielded significant improvements over the modest effects of BCG in protecting against infection or disease. On March 7-8, 2016, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on "The Impact of Mtb Immune Evasion on Protective Immunity: Implications for TB Vaccine Design" with the goal of defining immune mechanisms that could be targeted through novel research approaches, to inform vaccine design and immune therapeutic interventions for prevention of TB. The workshop addressed early infection events, the impact of Mtb evolution on the development and maintenance of an adaptive immune response, and the factors that influence protection against and progression to active disease. Scientific gaps and areas of study to revitalize and accelerate TB vaccine design were discussed and prioritized. These included a comprehensive evaluation of innate and Mtb-specific adaptive immune responses in the lung at different stages of disease; determining the role of B cells and antibodies (Abs) during Mtb infection; development of better assays to measure Mtb burden following exposure, infection, during latency and after treatment, and approaches to improving current animal models to study Mtb immunogenicity, TB disease and transmission. Copyright © 2017.

Rapid Serodiagnosis of Active Pulmonary Mycobacterium tuberculosis by Analysis of Results from Multiple Antigen-Specific Tests

PubMed Central

Okuda, Yoshinari; Maekura, Ryoji; Hirotani, Atsusi; Kitada, Seigo; Yoshimura, Kenji; Hiraga, Touru; Yamamoto, Yuoko; Itou, Masami; Ogura, Takeshi; Ogihara, Toshio

2004-01-01

We have prospectively analyzed three antigens for serodiagnosis of tuberculosis (TB). These antigens were tuberculous glycolipid antigen, lypoarabinomannan polysaccharide antigen, and antigen 60 (A60), which was derived from purified protein derivatives. Of the 131 patients with active pulmonary TB, 57 were both smear and culture negative and 14 had chronic active pulmonary TB that remained smear positive for >12 months of chemotherapy. One hundred twenty healthy adults were controls. The percentages of patients positive in all three tests were 58.8% for smear-positive active pulmonary TB and 71.4% for chronic active pulmonary TB. When the results of the three serodiagnostic tests were evaluated in combination, the sensitivity increased to 91.5% in patients with active pulmonary TB and to 86.0% in smear- and culture-negative patients. The false-positive rate of the three-test combination was 12.5% in the healthy control groups. In conclusion, it was not possible to detect all of the antibodies against antigenic substances in the cell walls of the tuberculous bacilli in the sera of all TB patients by using available serodiagnostic tests. However, the combined use of tests with three separate antigens maximizes the effectiveness of serodiagnosis. PMID:15004065

Severe hypovitaminosis D in active tuberculosis patients and its predictors.

PubMed

Wang, Qiuzhen; Liu, Yufeng; Ma, Yan; Han, Lei; Dou, Mei; Zou, Yue; Sun, Limei; Tian, Hong; Li, Tongxia; Jiang, Guofeng; Du, Baoli; Kou, Tingyan; Song, Jiaqi; Kok, Frans J; Schouten, Evert G

2018-06-01

Tuberculosis (TB) patients have a significant vitamin D deficiency (VDD) endemic, which may be closely related to the onset and progress of the disease. The comorbidity of diabetes (DM) and TB has posed an increasing challenge in recent years. However, the influence of DM on TB and the possible mechanism are still uncertain. We carried out this study to identify the nutritional status of vitamin D (VD) in TB patients in a northern city in China (latitude 36° N) and investigate the possible predictors of severe vitamin D deficiency (SVDD). A cross-sectional study including 461 active TB patients (192 with and 269 without DM) were randomly selected from Qingdao Chest Hospital from June 2015 to August 2016. We measured serum 25 hydroxyvitamin D [25(OH)D], and investigated the association between sociodemographic, dietary intake, DM, body mass index (BMI), severity of initial TB signs and symptoms (TB score) and VD status. Multivariate logistic regression analysis was used to define the possible predictors of SVDD. The median serum 25(OH)D concentration was 8.50 ng/mL. Of the 461 TB patients included, 383 (83.1%) had VDD [25(OH)D < 20 ng/mL], and 217 (47.1%) had SVDD [25(OH)D < 8 ng/mL]. The variables associated with serum 25(OH)D concentrations were DM, outdoor activity level, TB score and BMI (p < 0.05). Patients with severe TB score had nearly 5 fold higher risk of having SVDD compared with those in mild subgroup [OR (95% CI) = 4.919 (2.644-9.150), p < 0.001]. Low outdoor activity level also increased the odds of SVDD, while DM and high fish consumption showed protect effects. Severe hypovitaminosis D is prevalent in active TB patients, and the main predictors of SVDD were severe TB score, low outdoor activity, inadequate fish consumption. Lowered serum 25(OH)D may be associated with increased risk of TB in DM. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Early Whole Blood Transcriptional Signatures Are Associated with Severity of Lung Inflammation in Cynomolgus Macaques with Mycobacterium tuberculosis Infection.

PubMed

Gideon, Hannah P; Skinner, Jason A; Baldwin, Nicole; Flynn, JoAnne L; Lin, Philana Ling

2016-12-15

Whole blood transcriptional profiling offers great diagnostic and prognostic potential. Although studies identified signatures for pulmonary tuberculosis (TB) and transcripts that predict the risk for developing active TB in humans, the early transcriptional changes immediately following Mycobacterium tuberculosis infection have not been evaluated. We evaluated the gene expression changes in the cynomolgus macaque model of TB, which recapitulates all clinical aspects of human M. tuberculosis infection, using a human microarray and analytics platform. We performed genome-wide blood transcriptional analysis on 38 macaques at 11 postinfection time points during the first 6 mo of M. tuberculosis infection. Of 6371 differentially expressed transcripts between preinfection and postinfection, the greatest change in transcriptional activity occurred 20-56 d postinfection, during which fluctuation of innate and adaptive immune response-related transcripts was observed. Modest transcriptional differences between active TB and latent infection were observed over the time course with substantial overlap. The pattern of module activity previously published for human active TB was similar in macaques with active disease. Blood transcript activity was highly correlated with lung inflammation (lung [ 18 F]fluorodeoxyglucose [FDG] avidity) measured by positron emission tomography and computed tomography at early time points postinfection. The differential signatures between animals with high and low lung FDG were stronger than between clinical outcomes. Analysis of preinfection signatures of macaques revealed that IFN signatures could influence eventual clinical outcomes and lung FDG avidity, even before infection. Our data support that transcriptional changes in the macaque model are translatable to human M. tuberculosis infection and offer important insights into early events of M. tuberculosis infection. Copyright © 2016 by The American Association of Immunologists, Inc.

The effectiveness and cost-effectiveness of screening for active tuberculosis among migrants in the EU/EEA: a systematic review.

PubMed

Greenaway, Christina; Pareek, Manish; Abou Chakra, Claire-Nour; Walji, Moneeza; Makarenko, Iuliia; Alabdulkarim, Balqis; Hogan, Catherine; McConnell, Ted; Scarfo, Brittany; Christensen, Robin; Tran, Anh; Rowbotham, Nick; Noori, Teymur; van der Werf, Marieke J; Pottie, Kevin; Matteelli, Alberto; Zenner, Dominik; Morton, Rachael L

2018-04-01

The foreign-born population make up an increasing and large proportion of tuberculosis (TB) cases in European Union/European Economic Area (EU/EEA) low-incidence countries and challenge TB elimination efforts. Methods : We conducted a systematic review to determine effectiveness (yield and performance of chest radiography (CXR) to detect active TB, treatment outcomes and acceptance of screening) and a second systematic review on cost-effectiveness of screening for active TB among migrants living in the EU/EEA. Results : We identified six systematic reviews, one report and three individual studies that addressed our aims. CXR was highly sensitive (98%) but only moderately specific (75%). The yield of detecting active TB with CXR screening among migrants was 350 per 100,000 population overall but ranged widely by host country (110-2,340), migrant type (170-1,192), TB incidence in source country (19-336) and screening setting (220-1,720). The CXR yield was lower (19.6 vs 336/100,000) and the numbers needed to screen were higher (5,076 vs 298) among migrants from source countries with lower TB incidence (≤ 50 compared with ≥ 350/100,000). Cost-effectiveness was highest among migrants originating from high (> 120/100,000) TB incidence countries. The foreign-born had similar or better TB treatment outcomes than those born in the EU/EEA. Acceptance of CXR screening was high (85%) among migrants. Discussion : Screening programmes for active TB are most efficient when targeting migrants from higher TB incidence countries. The limited number of studies identified and the heterogeneous evidence highlight the need for further data to inform screening programmes for migrants in the EU/EEA.

Opportunities and challenges for HIV care in overlapping HIV and TB epidemics.

PubMed

Havlir, Diane V; Getahun, Haileyesus; Sanne, Ian; Nunn, Paul

2008-07-23

Tuberculosis (TB) and the emerging multidrug-resistant TB epidemic represent major challenges to human immunodeficiency virus (HIV) care and treatment programs in resource-limited settings. Tuberculosis is a major cause of mortality among patients with HIV and poses a risk throughout the course of HIV disease, even after successful initiation of antiretroviral therapy (ART). Progress in the implementation of activities directed at reducing TB burden in the HIV population lags far behind global targets. HIV programs designed for longitudinal care are ideally suited to implement TB control measures and have no option but to address TB vigorously to save patient lives, to safeguard the massive investment in HIV treatment, and to curb the global TB burden. We propose a framework of strategic actions for HIV care programs to optimally integrate TB into their services. The core activities of this framework include intensified TB case finding, treatment of TB, isoniazid preventive treatment, infection control, administration of ART, TB recording and reporting, and joint efforts of HIV and TB programs at the national and local levels.

Working towards TB elimination the WHO Regional Strategic Plan (2006-2015).

PubMed

Nair, Nani; Cooreman, Erwin

2006-03-01

DOTS has expanded rapidly in the South-East Asia Region over the period of the Partnership's first Global Plan (2001-2005), with almost 100% geographical coverage achieved in 2005. All countries have made impressive progress in improving coverage and quality. This progress has been made possible through strong political commitment and large investments in TB control for improved infrastructure, reliable drug supply, increased staffing, improved laboratory services, and intensified training and supervision. Accomplishing the objectives outlined in this document will require sustaining the progress in all countries and particularly in the five high burden countries for achieving major regional and global impact. National TB programmes will need to be supported to maintain or surpass the 70% case detection and 85% treatment success rates. The achievement of the TB-related targets linked to the MDGs will also depend on how effectively initiatives such as DOTS-Plus, PPM DOTS and interventions for TB/ HIV among others, are implemented. National governments and development partners must fulfill their commitments to mobilizing and sustaining adequate resources to support the full range of activities envisaged. The benefits of full and effective implementation of all the planned interventions would be substantial. These will result in 20 to 25 million TB cases being treated in DOTS program mes and more than 150 000 drug-resistant cases receiving treatment through DOTS-Plus during the period 2006-2015. In addition, at least 250 000 HIV-infected TB patients may also receive anti-retroviral therapy. As a consequence, the prevalence of TB is expected to fall below 175/100 000 and the number of TB deaths is expected to fall to between 100 000 and 150 000 per year. There would also be substantial economic benefits given that TB disproportionately affects adults in their most productive years. Considering these aspects, it is expected that the TB incidence will decline significantly during this period so that the Millennium Development Goals would be met by or ahead of 2015.

High Incidence of Tuberculosis Infection in Rheumatic Diseases and Impact for Chemoprophylactic Prevention of Tuberculosis Activation during Biologics Therapy

PubMed Central

Bai, Fengmin; Zhang, Shu; Jiang, Ting; Shen, Jie; Zhu, Qi; Yue, Tao; Shao, Lingyun; Gao, Yan; Feng, Yun; Weng, Xinhua; Zou, Hejian; Zhang, Ying

2013-01-01

We conducted a long-term follow-up study in patients with rheumatic diseases who were candidates for biologics treatment to evaluate the effects of biologic agents on the risk of tuberculosis infection and the effect of prophylactic treatment on tuberculosis activation. One hundred one patients with rheumatic diseases who were candidates for biologics treatment were recruited, and 57 healthy subjects were recruited as controls. Tuberculin skin test (TST) and the T-SPOT.TB test were performed for all subjects at baseline. Follow-up testing by the T-SPOT.TB assay was performed every 6 months in patients with rheumatic diseases and at 2 years of recruitment in the healthy controls. In patients with rheumatic diseases and healthy controls, the TST-positive (induration, ≥10 mm) rates were 37.6% (38/101) and 34.0% (18/53), respectively (P > 0.05), while the T-SPOT.TB-positive rates were 46.5% (47/101) and 21.1 (12/57), respectively (P = 0.0019). Fifty-two patients were followed up at month 6 with a T-SPOT.TB-positive rate of 40.4%, and 49 were followed up for ≥12 months with a T-SPOT.TB-positive rate of 36.7%, with no significant difference in the positive rate at different time points including baseline (P > 0.05). Long-term follow-up revealed that conversion to T-SPOT.TB positivity occurred only in the biologics treatment group, with a positive conversion rate of 11.2% (4/38). Most importantly, no latent tuberculosis developed into active tuberculosis during follow-up with T-SPOT.TB screening and preemptive treatment with isoniazid. Biologics treatment appears to increase the risk of tuberculosis infection. However, tuberculosis activation could be prevented by preemptive isoniazid treatment in patients with latent tuberculosis infection while receiving biologics therapy. PMID:23554465

Is Universal Screening Necessary? Incidence of Tuberculosis among Tibetan Refugees Arriving in Calgary, Alberta.

PubMed

Lim, Rachel; Jarand, Julie; Field, Stephen K; Fisher, Dina

2016-01-01

Background . Canadian policy requires refugees with a history of tuberculosis (TB) or abnormal chest radiograph to be screened after arrival for TB. However, Tibetan refugees are indiscriminately screened, regardless of preimmigration assessment. We sought to determine the incidence of latent (LTBI) and active TB, as well as treatment-related outcomes and associations between preimmigration factors and TB infection among Tibetan refugees arriving in Calgary, Alberta. Design . Retrospective cohort study including Tibetan refugees arriving between 2014 and 2016. Associations between preimmigration factors and incidence of latent and active TB were determined using Chi-square tests. Results . Out of 180 subjects, 49 percent had LTBI. LTBI was more common in migrants 30 years of age or older ( P = 0.009). Treatment initiation and completion rates were high at 90 percent and 76 percent, respectively. No associations between preimmigration factors and treatment completion were found. A case of active TB was detected and treated. Conclusion . Within this cohort, the case of active TB would have been detected through the usual postsurveillance process due to a history of TB and abnormal chest radiograph. Forty-nine percent had LTBI, compared to previously quoted rates of 97 percent. Tibetan refugees should be screened for TB in a similar manner to other refugees resettling in Canada.

Muscle volume is related to trabecular and cortical bone architecture in typically developing children.

PubMed

Bajaj, Deepti; Allerton, Brianne M; Kirby, Joshua T; Miller, Freeman; Rowe, David A; Pohlig, Ryan T; Modlesky, Christopher M

2015-12-01

Muscle is strongly related to cortical bone architecture in children; however, the relationship between muscle volume and trabecular bone architecture is poorly studied. The aim of this study was to determine if muscle volume is related to trabecular bone architecture in children and if the relationship is different than the relationship between muscle volume and cortical bone architecture. Forty typically developing children (20 boys and 20 girls; 6 to 12y) were included in the study. Measures of trabecular bone architecture [i.e., apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th) and trabecular separation (appTb.Sp)] in the distal femur, cortical bone architecture [cortical volume, total volume, section modulus (Z) and polar moment of inertia (J)] in the midfemur, muscle volume in the midthigh and femur length were assessed using magnetic resonance imaging. Total physical activity and moderate-to-vigorous physical activity were assessed using an accelerometer-based activity monitor worn around the waist for four days. Calcium intake was assessed using diet records. Relationships among the measures were tested using multiple linear regression analysis. Muscle volume was moderately-to-strongly related to measures of trabecular bone architecture [appBV/TV (r=0.81), appTb.N (r=0.53), appTb.Th (r=0.67), appTb.Sp (r=-0.71); all p<0.001] but more strongly related to measures of cortical bone architecture [cortical volume (r=0.96), total volume (r=0.94), Z (r=0.94) and J (r=0.92; all p<0.001)]. Similar relationships were observed between femur length and measures of trabecular (p<0.01) and cortical (p<0.001) bone architecture. Sex, physical activity and calcium intake were not related to any measure of bone architecture (p>0.05). Because muscle volume and femur length were strongly related (r=0.91, p<0.001), muscle volume was scaled for femur length (muscle volume/femur length(2.77)). When muscle volume/femur length(2.77) was included in a regression model with femur length, sex, physical activity and calcium intake, muscle volume/femur length(2.77) was a significant predictor of appBV/TV, appTb.Th and appTb.Sp (partial r=0.44 to 0.49, p<0.05) and all measures of cortical bone architecture (partial r=0.47 to 0.54; p<0.01). The findings suggest that muscle volume in the midthigh is related to trabecular bone architecture in the distal femur of typically developing children. The relationship is weaker than the relationship between muscle volume in the midthigh and cortical bone architecture in the midfemur, but the discrepancy is driven, in large part, by the greater dependence of cortical bone architecture measures on femur length. Copyright © 2015. Published by Elsevier Inc.

Delamanid Kills Dormant Mycobacteria In Vitro and in a Guinea Pig Model of Tuberculosis.

PubMed

Chen, Xiuhao; Hashizume, Hiroyuki; Tomishige, Tatsuo; Nakamura, Izuru; Matsuba, Miki; Fujiwara, Mamoru; Kitamoto, Ryuki; Hanaki, Erina; Ohba, Yoshio; Matsumoto, Makoto

2017-06-01

Tuberculosis (TB) treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug susceptibilities. Drugs with broad activity are urgently needed. This study aimed to evaluate delamanid's activity against growing or dormant bacilli in vitro as well as in vivo Cultures of Mycobacterium bovis BCG Tokyo under aerobic and anaerobic conditions were used to study the activity of delamanid against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above concentrations of 0.016 and 0.4 mg/liter, respectively. To evaluate delamanid's antituberculosis activity in vivo , we used a guinea pig model of chronic TB infection in which the lung lesions were similar to those in human TB disease. In the guinea pig TB model, a daily dose of 100 mg delamanid/kg of body weight for 4 or 8 weeks demonstrated strong bactericidal activity against Mycobacterium tuberculosis Importantly, histological examination revealed that delamanid killed TB bacilli within hypoxic lesions of the lung. The combination regimens containing delamanid with rifampin and pyrazinamide or delamanid with levofloxacin, ethionamide, pyrazinamide, and amikacin were more effective than the standard regimen (rifampin, isoniazid, and pyrazinamide). Our data show that delamanid is effective in killing both growing and dormant bacilli in vitro and in the guinea pig TB model. Adding delamanid to current TB regimens may improve treatment outcomes, as demonstrated in recent clinical trials with pulmonary multidrug-resistant (MDR) TB patients. Delamanid may be an important drug for consideration in the construction of new regimens to shorten TB treatment duration. Copyright © 2017 American Society for Microbiology.

Occupational exposure to tuberculosis--OSHA. Proposed rule and notice of public hearing.

PubMed

1997-10-17

The Occupational Safety and Health Administration is proposing a health standard, to be promulgated under section 6(b) of the Occupational Safety and Health Act of 1970, 29 U.S.C. 655, to control occupational exposure to tuberculosis (TB). TB is a communicable, potentially lethal disease that afflicts the most vulnerable members of our society: the poor, the sick, the aged, and the homeless. As many as 13 million U.S. adults are presently believed to be infected with TB; over time, more than 1 million of these individuals may develop active TB disease and transmit the infection to others. TB remains a major health problem with 22,813 active cases reported in the U.S. in 1995. A number of outbreaks of this disease have occurred among workers in health care settings, as well as other work settings, in recent years. To add to the seriousness of the problem, some of these outbreaks have involved the transmission of multidrug-resistant strains of Mycobacterium tuberculosis, which are often fatal. Although it is the responsibility of the U.S. Public Health Service to address the problem of tuberculosis in the general U.S. population, OSHA is solely responsible for protecting the health of workers exposed to TB as a result of their job. OSHA estimates that more than 5 million U.S. workers are exposed to TB in the course of their work: in hospitals, homeless shelters, nursing homes, and other work settings. Because active TB is endemic in many U.S. populations, including groups in both urban and rural areas, workers who come into contact with diseased individuals are at risk of contracting the disease themselves. The risk confronting these workers as a result of their contact with TB-infected individuals may be as high as 10 times the risk to the general population. Although the number of reported cases of active TB has slowly begun to decline after a resurgence between 1985-1992, 16 states reported an increase in the number of TB cases in 1995, compared with 1994. Based on a review of the data, OSHA has preliminarily concluded that workers in hospitals, nursing homes, hospices, correctional facilities, homeless shelters, and certain other work settings are at significant risk of incurring TB infection while caring for their patients and clients or performing certain procedures. To reduce this occupational risk, OSHA is proposing a standard that would require employers to protect TB-exposed employees by means of infection prevention and control measures that have been demonstrated to be highly effective in reducing or eliminating job-related TB infections. These measures include the use of respirators when performing certain high hazard procedures on infectious individuals, procedures for the early identification and treatment of TB infection, isolation of individuals with infectious TB in rooms designed to protect those in the vicinity of the room from contact with the microorganisms causing TB, and medical follow-up for occupationally exposed workers who become infected. OSHA has preliminarily determined that the engineering, work practice, and administrative controls, respiratory protection, training, medical surveillance, and other provisions of the proposed standard are technologically and economically feasible for facilities in all affected industries.

Frequent Detection of Latent Tuberculosis Infection among Aged Underground Hard Coal Miners in the Absence of Recent Tuberculosis Exposure

PubMed Central

Ringshausen, Felix C.; Nienhaus, Albert; Schablon, Anja; Torres Costa, José; Knoop, Heiko; Hoffmeyer, Frank; Bünger, Jürgen; Merget, Rolf; Harth, Volker; Schultze-Werninghaus, Gerhard; Rohde, Gernot

2013-01-01

Background Miners are at particular risk for tuberculosis (TB) infection due to exposure to silica dust and silicosis. The objectives of the present observational cohort study were to determine the prevalence of latent TB infection (LTBI) among aged German underground hard coal miners with silicosis or chronic obstructive pulmonary disease (COPD) using two commercial interferon-gamma release assays (IGRAs) and to compare their performance with respect to predictors of test positivity. Methods Between October 2008 and June 2010, miners were consecutively recruited when routinely attending pneumoconiosis clinics for an expert opinion. Both IGRAs, the QuantiFERON®-TB Gold In-Tube (QFT) and the T-SPOT®.TB (T-SPOT), were performed at baseline. A standardized clinical interview was conducted at baseline and at follow-up. The cohort was prospectively followed regarding the development of active TB for at least two years after inclusion of the last study subject. Independent predictors of IGRA positivity were calculated using logistic regression. Results Among 118 subjects (mean age 75 years), none reported recent exposure to TB. Overall, the QFT and the T-SPOT yielded similarly high rates of positive results (QFT: 46.6%; 95% confidence interval 37.6–55.6%; T-SPOT: 61.0%; 95% confidence interval 52.2–69.8%). Positive results were independently predicted by age ≥80 years and foreign country of birth for both IGRAs. In addition, radiological evidence of prior healed TB increased the chance of a positive QFT result fivefold. While 28 subjects were lost to follow-up, no cases of active TB occurred among 90 subjects during an average follow-up of >2 years. Conclusions Considering the high prevalence of LTBI, the absence of recent TB exposure, and the currently low TB incidence in Germany, our study provides evidence for the persistence of specific interferon-gamma responses even decades after putative exposure. However, the clinical value of current IGRAs among our study population, although probably limited, remains uncertain. PMID:24312620

Prevalence of smear positive pulmonary tuberculosis among prisoners in North Gondar Zone Prison, northwest Ethiopia.

PubMed

Moges, Beyene; Amare, Bemnet; Asfaw, Fanaye; Tesfaye, Wogahta; Tiruneh, Moges; Belyhun, Yeshambel; Mulu, Andargachew; Kassu, Afework

2012-12-15

People concentrated in congregated systems, such as prisons, are important but often neglected reservoirs for TB transmission, and threaten those in the outside community. Therefore, this study was conducted to determine the prevalence of tuberculosis in a prison system of North Gondar Zone. An active case-finding survey in North Gondar Prison was carried out from March to May 2011. All prison inmates who had history of cough for at least a week were included in the study. Three morning sputum samples were collected from suspected inmates and examined through fluorescence microscopy. Fine needle aspiration cytology was done for those having significant lymphadenopathy. Pre and post HIV test counseling was provided after written consent. Binary logistic and multivariable analysis was performed using SPSS version 16. A total of 250 prisoners were included in the survey. Among these, 26 (10.4%) prisoners were found to have TB giving a point prevalence of 1482.3 per 100,000 populations of smear positive TB among the TB suspects. All the inmates who participated in the study volunteered for HIV testing and a total of 19(7.6%) inmates were found to be reactive for the HIV antibody test amongst of which 9(47.4%) had TB co-infection. The prevalence of HIV infection in the TB infected inmates was found to be 34.6% (9/26). From the 26 TB cases identified 12 (46.2%) were having under nutrition (BMI < 18.5kg/m(2)). There is high prevalence of TB in North Gondar Prison with possible active transmission of TB within the prison. There was a high prevalence of HIV among the TB suspects. Strong cooperation between prison authorities and the national tuberculosis control programmes is urgently required to develop locally appropriate interventions to reduce transmission. The determinants for poor nutrition in the prison need also further investigation.

Clinical characteristics, drug resistance, and treatment outcomes among tuberculosis patients with diabetes in Peru.

PubMed

Magee, M J; Bloss, E; Shin, S S; Contreras, C; Huaman, H Arbanil; Ticona, J Calderon; Bayona, J; Bonilla, C; Yagui, M; Jave, O; Cegielski, J P

2013-06-01

Diabetes is a risk factor for active tuberculosis (TB). Data are limited regarding the association between diabetes and TB drug resistance and treatment outcomes. We examined characteristics of TB patients with and without diabetes in a Peruvian cohort at high risk for drug-resistant TB. Among TB patients with diabetes (TB-DM), we studied the association between diabetes clinical/management characteristics and TB drug resistance and treatment outcomes. During 2005-2008, adults with suspected TB with respiratory symptoms in Lima, Peru, who received rapid drug susceptibility testing (DST), were prospectively enrolled and followed during treatment. Bivariate and Kaplan-Meier analyses were used to examine the relationships of diabetes characteristics with drug-resistant TB and TB outcomes. Of 1671 adult TB patients enrolled, 186 (11.1%) had diabetes. TB-DM patients were significantly more likely than TB patients without diabetes to be older, have had no previous TB treatment, and to have a body mass index (BMI) >18.5 kg/m(2) (p<0.05). In patients without and with previous TB treatment, the prevalence of multidrug-resistant TB was 23% and 26%, respectively, among patients without diabetes, and 12% and 28%, respectively, among TB-DM patients. Among 149 TB-DM patients with DST results, 104 (69.8%) had drug-susceptible TB and 45 (30.2%) had drug-resistant TB, of whom 29 had multidrug-resistant TB. There was no association between diabetes characteristics and drug-resistant TB. Of 136 TB-DM patients with outcome information, 107 (78.7%) had a favorable TB outcome; active diabetes management was associated with a favorable outcome. Diabetes was common in a cohort of TB patients at high risk for drug-resistant TB. Despite prevalent multidrug-resistant TB among TB-DM patients, the majority had a favorable TB treatment outcome. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Evaluation of coexistence of cancer and active tuberculosis; 16 case series.

PubMed

Çakar, Beyhan; Çiledağ, Aydın

2018-01-01

Tuberculosis is an important risk factor for cancer. Pulmonary TB and lung cancer(LC) may mimic each other especially in the aspect of the clinical and radiological features. The aim of the study was to evaluate the features and risk factors of cases with coexistence cancer and active TB. We retrospectively reviewed the medical records of patients with coexisting TB and cancer a period from 2009 to 2014. We evaluated demographic data, the ways diagnosis of TB cases, the location of TB and cancer, TB treatment results of the cases. We recorded 374 TB cases in our dyspensary at this study period. In 16 (4%) of these cases, a coexistence of cancer and TB was detected. The male/female ratio was 12/4. The mean age was 62,12 ± 15,13 years. There were TST results except three cases. There were ten pulmonary TB and six extra-pulmonary TB (four peripheral lymphadenopathy TB, one abdominal TB lymphadenopathy and one salivary gland TB). Cancer types were as follows; eight lung cancer, two breast cancer, one base of tongue, one endometrium cancer, one hypopharyngeal cancer, one stomach cancer, one bladder cancer and one maxillary cancer. Diagnosis of all cases was confirmed by bacteriologic and/or histopathological examination. Squamous cell carcinoma was the most common type of cancers. This rate was 9/16. All TB cases were new. There were risk factors out of two case in the cases. Five cases were died during TB treatment. Others completed TB treatment without any complication. In our study, the coexistence of LC and pulmonary TB was more common. The local immunity is deteriorated in cancer cases. If there is pulmonary infiltrates in lung or peripheral lymphadenopathy, we must search tuberculosis too out of metastatic lesion and other infectious diseases. We should not make delay in the diagnosis of active TB in cancer cases.

Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis.

PubMed

Martineau, Adrian R

2012-02-01

Tuberculosis (TB) is a major cause of mortality, responsible for 1·68 million deaths worldwide in 2009. The global prevalence of latent Mycobacterium tuberculosis infection is estimated to be 32%, and this carries a 5-20% lifetime risk of reactivation disease. The emergence of drug-resistant organisms necessitates the development of new agents to enhance the response to antimicrobial therapy for active TB. Vitamin D was used to treat TB in the pre-antibiotic era, and its active metabolite, 1,25-dihydoxyvitamin D, has long been known to enhance the immune response to mycobacteria in vitro. Vitamin D deficiency is common in patients with active TB, and several clinical trials have evaluated the role of adjunctive vitamin D supplementation in its treatment. Results of these studies are conflicting, reflecting variation between studies in baseline vitamin D status of participants, dosing regimens and outcome measures. Vitamin D deficiency is also recognised to be highly prevalent among people with latent M. tuberculosis infection in both high- and low-burden settings, and there is a wealth of observational epidemiological evidence linking vitamin D deficiency with increased risk of reactivation disease. Randomised controlled trials of vitamin D supplementation for the prevention of active TB have yet to be performed, however. The conduct of such trials is a research priority, given the safety and low cost of vitamin D supplementation, and the potentially huge public health consequences of positive results.

Plan to combat extensively drug-resistant tuberculosis: recommendations of the Federal Tuberculosis Task Force.

PubMed

2009-02-13

An estimated one third of the world's population is infected with Mycobacterium tuberculosis, and nearly 9 million persons develop disease caused by M. tuberculosis each year. Although tuberculosis (TB) occurs predominantly in resource-limited countries, it also occurs in the United States. During 1985-1992, the United States was confronted with an unprecedented TB resurgence. This resurgence was accompanied by a rise in multidrug-resistant TB (MDR TB), which is defined as TB that is resistant to the two most effective first-line therapeutic drugs, isoniazid and rifampin. In addition, virtually untreatable strains of M. tuberculosis are emerging globally. Extensively drug-resistant (XDR) TB is defined as MDR TB that also is resistant to the most effective second-line therapeutic drugs used commonly to treat MDR TB: fluoroquinolones and at least one of three injectable second-line drugs used to treat TB (amikacin, kanamycin, or capreomycin). XDR TB has been identified in all regions of the world, including the United States. In the United States, the cost of hospitalization for one XDR TB patient is estimated to average $483,000, approximately twice the cost for MDR TB patients. Because of the limited responsiveness of XDR TB to available antibiotics, mortality rates among patients with XDR TB are similar to those of TB patients in the preantibiotic era. In January 1992, CDC convened a Federal TB Task Force to draft an action plan to improve prevention and control of drug-resistant TB in the United States (CDC. National action plan to combat multidrug-resistant tuberculosis. MMWR 1992;41([No. RR-11]). In November 2006, CDC reconvened the Task Force to draft an updated action plan to address the issue of MDR TB and XDR TB. Task Force members were divided into nine response areas and charged with articulating the most pressing problems, identifying barriers to improvement, and recommending specific action steps to improve prevention and control of XDR TB within their respective areas. Although the first priority of the Federal TB Task Force convened in 2006 was to delineate objectives and action steps to address MDR TB and XDR TB domestically, members recognized the necessity for TB experts in the United States to work with the international community to help strengthen TB control efforts globally. TB represents a substantial public health problem in low- and middle-income countries, many of which might benefit from assistance by the United States. In addition, the global TB epidemic directly affects the United States because the majority of all cases of TB and 80% of cases of MDR TB reported in the United States occur among foreign-born persons. For these reasons, the Action Plan also outlines potential steps that U.S. government agencies can take to help solve global XDR TB problems. Unless the fundamental causes of MDR TB and XDR TB are addressed in the United States and internationally, the United States is likely to experience a growing number of cases of MDR TB and XDR TB that will be difficult, if not impossible, to treat or prevent. The recommendations provided in this report include specific action steps and new activities that will require additional funding and a renewed commitment by government and nongovernment organizations involved in domestic and international TB control efforts to be implemented effectively. The Federal TB Task Force will coordinate activities of various federal agencies and partner with state and local health departments, nonprofit and TB advocacy organizations in implementing this plan to control and prevent XDR TB in the United States and to contribute to global efforts in the fight against this emerging public health crisis.

[Thoracic manifestation of tuberculosis].

PubMed

Kienzl-Palma, D; Prosch, H

2016-10-01

Tuberculosis (TB) is a granulomatous disease caused by Mycobacterium tuberculosis and transmission is via an airborne route by droplet infection. In the majority of cases patients have thoracic TB, which most frequently presents with hilar lymphadenopathy and pulmonary manifestation. Due to the rise in incidence of TB in central Europe to be expected over the coming years, it is essential to be acquainted with the radiological manifestations of pulmonary TB, particularly to be able to discriminate active from inactive TB. Due to the use of molecular techniques entailing DNA fingerprinting, the traditional classification of TB in primary and postprimary TB is being challenged. These genetic studies have revealed that variations in the clinical and radiographic appearance of TB are mainly affected by the immune status of the patients. Due to the low prevalence of TB in central Europe and the wide variation of radiological presentations, the diagnosis and therapy of TB is often delayed. In this article, the radiographic manifestations of thoracic TB are summarized and discussed. Together with the medical history and bacteriological tests, chest X‑ray imaging and computed tomography (CT) play a major role not only in the detection of TB but also in the follow-up during and after therapy. Chest X‑radiographs should be the primary diagnostic method in patients with suspected TB in screening as well as for diagnosis and therapy monitoring. The use of CT is more sensitive than chest radiographs and is frequently performed after chest radiographs to obtain detailed information about subtle parenchymal changes or lymph node manifestation. When active TB is suspected CT should be performed. Tree in bud, lobular consolidations, centrilobular nodules, cavities and ground-glass opacification are typical changes in active TB.

Simultaneous depletion of Atm and Mdl rebalances cytosolic Fe-S cluster assembly but not heme import into the mitochondrion of Trypanosoma brucei.

PubMed

Horáková, Eva; Changmai, Piya; Paris, Zdeněk; Salmon, Didier; Lukeš, Julius

2015-11-01

ABC transporter mitochondrial 1 (Atm1) and multidrug resistance-like 1 (Mdl) are mitochondrial ABC transporters. Although Atm1 was recently suggested to transport different forms of glutathione from the mitochondrion, which are used for iron-sulfur (Fe-S) cluster maturation in the cytosol, the function of Mdl remains elusive. In Trypanosoma brucei, we identified one homolog of each of these genes, TbAtm and TbMdl, which were downregulated either separately or simultaneously using RNA interference. Individual depletion of TbAtm and TbMdl led to limited growth defects. In cells downregulated for TbAtm, the enzymatic activities of the Fe-S cluster proteins aconitase and fumarase significantly decreased in the cytosol but not in the mitochondrion. Downregulation of TbMdl did not cause any change in activities of the Fe-S proteins. Unexpectedly, the simultaneous downregulation of TbAtm and TbMdl did not result in any growth defect, nor were the Fe-S cluster protein activities altered in either the cytosolic or mitochondrial compartments. Additionally, TbAtm and TbMdl were able to partially restore the growth of the Saccharomyces cerevisiae Δatm1 and Δmdl2 null mutants, respectively. Because T. brucei completely lost the heme b biosynthesis pathway, this cofactor has to be obtained from the host. Based on our results, TbMdl is a candidate for mitochondrial import of heme b, which was markedly decreased in both TbMdl and TbAtm + TbMdl knockdowns. Moreover, the levels of heme a were strongly decreased in the same knockdowns, suggesting that TbMdl plays a key role in heme a biosynthesis, thus affecting the overall heme homeostasis in T. brucei. © 2015 FEBS.

[USE OF QuantiFERON-TB Gold in Tube AND T-SPOT.TB FOR DIAGNOSING PATIENTS WITH SUSPECTED PULMONARY TUBERCULOSIS].

PubMed

Okimoto, Niro; Kurihara, Takeyuki; Miyashita, Naoyuki

2016-04-01

We analyzed the use of QFT-TB Gold in Tube and T-SPOT.TB in diagnosing patients with suspected pulmonary tuberculosis. We evaluated 122 patients with suspected pulmonary tuberculosis (where chest X-ray showed consolidation or. tumor shadow in predilection sites of pulmonary tuberculosis and through contact investigation). QFT-TB Gold and T-SPOT.TB were performed for all the patients. The positive response rate and history of pulmonary tuberculosis in patients who showed positive results for the tests were evaluated. Ninteen patients showed positive results for QFT-TB Gold, and 9, for T-SPOT.TB. Four patients showed positive results for QFT-TB Gold, and 3, for T-SPOT.TB in 4 patients with active tuberculosis. The patients without active tuberculosis whose IGRAs were positive (old pulmonary tuberculosis, Mycobacterium avium cmplex, pneumonia, lung cancer, pulmonary sequestration, bronchiectasis) had a past history of pulmonary tuberculosis. The positive result rate of QFT?-TB Gold was higher than that of T-SPOT.TB in the subjects with suspected pulmonary tuberculosis. We think that QFT-TB Gold reflected the past history of pulmonary tuberculosis.

Epidemiology of HIV-TB in Asia.

PubMed

Narain, Jai P; Lo, Ying-Ru

2004-10-01

Tuberculosis (TB) has, for centuries, continued to remain a public health problem of enormous importance, particularly in the developing world, taking a heavy toll of those at their prime of life. The emergence of human immunodeficiency virus (HIV infection) and its close association with TB poses an even greater challenge to the health systems in general and TB programmes in particular, in African and Asian countries. HIV is considered to be the most potent risk factor for progression to active TB among those infected both with TB and HIV; as a result, TB is the most common life threatening opportunistic infection associated with HIV, and biggest cause of death among patients with acquired immunodeficiency syndrome (AIDS). In areas hard-hit by HIV, TB is increasing, leading to greater case load, thereby overstretching the already fragile health infrastructure. The deadly relationship between HIV and TB, each potentiating the effect of the other, requires a clearly defined strategy taking into consideration the natural history of the co-infection and its progression to clinical TB (and AIDS). It is clear that the only way to fight this is by bringing the two programmes to join forces and work creatively and innovatively. The strategy should include not only preventing HIV through community-based behavioural interventions and limiting progression to clinical TB through the use of isoniazid preventive therapy, but also early diagnosis and treatment of HIV-associated TB and AIDS using DOTS strategy and combination antiretroviral therapy respectively. The strategy probably would not succeed unless both the programmes are first strengthened before attempting to forge collaboration based on mutual strengths and comparative advantages. In addition, mobilizing national and international response, building partnerships and mobilizing resources will help a great deal in mounting an appropriate and effective response to HIV/TB in the Asian context.

Dynamic Changes in Pro- and Anti-Inflammatory Cytokine Profiles and Gamma Interferon Receptor Signaling Integrity Correlate with Tuberculosis Disease Activity and Response to Curative Treatment▿

PubMed Central

Sahiratmadja, Edhyana; Alisjahbana, Bachti; de Boer, Tjitske; Adnan, Iskandar; Maya, Anugrah; Danusantoso, Halim; Nelwan, Ronald H. H.; Marzuki, Sangkot; van der Meer, Jos W. M.; van Crevel, Reinout; van de Vosse, Esther; Ottenhoff, Tom H. M.

2007-01-01

Pro- and anti-inflammatory cytokines and their signaling pathways play key roles in protection from and pathogenesis of mycobacterial infection, and their balance and dynamic changes may control or predict clinical outcome. Peripheral blood cells' capacity to produce proinflammatory (tumor necrosis factor alpha [TNF-α], interleukin-12/23p40 [IL-12/23p40], and gamma interferon [IFN-γ]) and anti-inflammatory (IL-10) cytokines in response to Mycobacterium tuberculosis or unrelated stimuli (lipopolysaccharide, phytohemagglutinin) was studied in 93 pulmonary tuberculosis (TB) patients and 127 healthy controls from Indonesia. Their cells' ability to respond to IFN-γ was examined to investigate whether M. tuberculosis infection can also inhibit IFN-γ receptor (IFN-γR) signaling. Although there was interindividual variability in the observed responses, the overall results revealed that M. tuberculosis-induced TNF-α and IFN-γ levels showed opposite trends. Whereas TNF-α production was higher in active-TB patients than in controls, IFN-γ production was strongly depressed during active TB, correlated inversely with TB disease severity, and increased during therapy. By contrast, mitogen-induced IFN-γ production, although lower in patients than in controls, did not change during treatment, suggesting an M. tuberculosis-specific and reversible component in the depression of IFN-γ. Depressed IFN-γ production was not due to decreased IL-12/IL-23 production. Importantly, IFN-γ-inducible responses were also significantly depressed during active TB and normalized during treatment, revealing disease activity-related and reversible impairment in IFN-γR signaling in TB. Finally, IFN-γ/IL-10 ratios significantly correlated with TB cure. Taken together, these results show that M. tuberculosis-specific stimulation of IFN-γ (but not TNF-α) production and IFN-γR signaling are significantly depressed in active TB, correlate with TB disease severity and activity, and normalize during microbiological TB cure. The depression of both IFN-γ production and IFN-γR signaling may synergize in contributing to defective host control in active TB. PMID:17145950

[The Enhanceing effect of IL-12 on phagocytosis and killing of Mycobacterium tuberculosis by neutrophils in tuberculosis patients].

PubMed

Jiang, Li-na; Yao, Chun-yan; Jin, Qi-li; He, Wen-xin; Li, Bai-qing

2011-11-01

To explore the effects of IL-12 on phagocytosis and killing of Mycobacterium tuberculosis by neutrophils or polymorphonuclear cells (PMNs) in tuberculosis patients. The fresh peripheral blood samples from TB patients and healthy adults were incubated with M.tb labeled with FITC, and the percentages of phagocytosis of M.tb by PMNs was measured by flow cytometry (FCM). The fresh peripheral blood samples were incubated with DCFH-DA, and with or without M.tb for different times, the percentage of activation and the ROS production of PMNs were measured by FCM. Whole blood samples were pretreated with IL-12, the changes of phagocytosis, activation and ROS production of PMNs were measured by FCM. The percentages of phagocytosis by PMNs, activation and ROS production of PMNs in both TB patients and healthy adults increased dependent on the time of incubation with M.tb. Only the phagocytosis of M.tb by PMNs at 5 min in TB patients of tuberculosis patients (51.82±6.93)% was obviously higher than that in healthy adults (47.20±4.26)%, (P<0.05). Pretreatment of whole blood with IL-12 before incubation with M.tb, the percentages of phagocytosis, activation and ROS production of PMNs in both TB patients and healthy adults increased in dose dependent manner, but no significant difference was found between both groups. The results indicated that the phagocytosis of M.tb and ROS production by PMNs in TB patients were almost the same as that in healthy controls, except for phagocytosis is higher at early stage. Furthermore, IL-12 can enhance the responsiveness to the phagocytosis and ROS production of PMNs.

The trenbolone acetate affects the immune system in rainbow trout, Oncorhynchus mykiss.

PubMed

Massart, Sophie; Redivo, Baptiste; Flamion, Enora; Mandiki, S N M; Falisse, Elodie; Milla, Sylvain; Kestemont, Patrick

2015-06-01

In aquatic systems, the presence of endocrine-disrupting chemicals (EDC) can disrupt the reproductive function but also the immune system of wildlife. Some studies have investigated the effects of androgens on the fish immune parameters but the mechanisms by which the xenoandrogens alter the immunity are not well characterized. In order to test the effects of trenbolone acetate (TbA) on fish immune system, we exposed rainbow trout male juveniles during three weeks to TbA levels at 0.1 and 1μg/L. The present results suggest that TbA impacts, in a tissue-dependent manner, the rainbow trout immunity by affecting primarily the humoral immunity. Indeed, TbA inhibited lysozyme activity in plasma and liver and enhanced the alternative complement pathway activity (ACH50) in kidney. In plasma, the modulation of the complement system was time-dependent. The mRNA expression of genes encoding some cytokines such as renal TGF-β1, TNF-α in skin and hepatic IL-1β was also altered in fish exposed to TbA. Regarding the cellular immunity, no effect was observed on the leucocyte population. However, the expression of genes involved in the development and maturation of lymphoid cells (RAG-1 and RAG-2) was decreased in TbA-treated fish. Among those effects, we suggest that the modulation of RAG-1 and mucus apolipoprotein-A1 gene expression as well as plasma and hepatic lysozyme activities are mediated through the action of the androgen receptor. All combined, we conclude that trenbolone affects the rainbow trout immunity. Copyright © 2015 Elsevier B.V. All rights reserved.

Daily and annual cycles in thermoregulatory behaviour and cardio-respiratory physiology of black and white tegu lizards.

PubMed

Sanders, Colin E; Tattersall, Glenn J; Reichert, Michelle; Andrade, Denis V; Abe, Augusto S; Milsom, William K

2015-12-01

This study was designed to determine the manner in which metabolism is suppressed during dormancy in black and white tegu lizards (Tupinambis merianae). To this end, heart rate (fH), respiration rate (fR), and deep body temperature (Tb) were continuously monitored in outdoor enclosures by radio-telemetry for nine months. There was a continuous decline in nighttime breathing and heart rate, at constant Tb, throughout the late summer and fall suggestive of an active metabolic suppression that developed progressively at night preceding the entrance into dormancy. During the day, however, the tegus still emerged to bask. In May, when the tegus made a behavioural commitment to dormancy, Tb (day and night) fell to match burrow temperature, accompanied by a further reduction in fH and fR. Tegus, under the conditions of this study, did arouse periodically during dormancy. There was a complex interplay between changes in fH and Tb associated with the direct effects of temperature and the indirect effects of thermoregulation, activity, and changes in metabolism. This interplay gave rise to a daily hysteresis in the fH/Tb relationship reflective of the physiological changes associated with warming and cooling as preferred Tb alternated between daytime and nighttime levels. The shape of the hysteresis curve varied with season along with changes in metabolic state and daytime and nighttime body temperature preferences.

Evaluation of the ICT Tuberculosis test for the routine diagnosis of tuberculosis

PubMed Central

Ongut, Gozde; Ogunc, Dilara; Gunseren, Filiz; Ogus, Candan; Donmez, Levent; Colak, Dilek; Gultekin, Meral

2006-01-01

Background Rapid and accurate diagnosis of tuberculosis (TB) is crucial to facilitate early treatment of infectious cases and thus to reduce its spread. To improve the diagnosis of TB, more rapid diagnostic techniques such as antibody detection methods including enzyme-linked immunosorbent assay (ELISA)-based serological tests and immunochromatographic methods were developed. This study was designed to evaluate the validity of an immunochromatographic assay, ICT Tuberculosis test for the serologic diagnosis of TB in Antalya, Turkey. Methods Sera from 72 patients with active pulmonary (53 smear-positive and 19 smear-negative cases) and eight extrapulmonary (6 smear-positive and 2 smear-negative cases) TB, and 54 controls from different outpatient clinics with similar demographic characteristics as patients were tested by ICT Tuberculosis test. Results The sensitivity, specificity, and negative predictive value of the ICT Tuberculosis test for pulmonary TB were 33.3%, 100%, and 52.9%, respectively. Smear-positive pulmonary TB patients showed a higher positivity rate for antibodies than smear-negative patients, but the difference was not statistically significant. Of the eight patients with extrapulmonary TB, antibody was detected in four patients. Conclusion Our results suggest that ICT Tuberculosis test can be used to aid TB diagnosis in smear-positive patients until the culture results are available. PMID:16504161

Multiplex analysis of plasma cytokines/chemokines showing different immune responses in active TB patients, latent TB infection and healthy participants.

PubMed

Yao, Xiangyang; Liu, Yongliang; Liu, Yang; Liu, Wei; Ye, Zhizhong; Zheng, Chao; Ge, Shengxiang

2017-12-01

Interferon gamma release assays (IGRAs) have been widely used to diagnose Mycobacterium tuberculosis (MTB) infection. However, IGRAs cannot discriminate between active TB patients and latent TB infection (LTBI), and the sensitivity of IGRAs for MTB infection is suboptimal. Here, we analyzed cytokines/chemokines in MTB antigen-stimulated and -unstimulated plasma samples to identify host biomarkers that are associated with active TB and MTB infection. Active TB patients, subjects with LTBI and healthy participants were recruited. Seventy-one soluble cytokines and chemokines were tested using Luminex liquid array-based multiplexed immunoassays. For the 71 examined factors, our results indicated that the unstimulated levels of IL-8 Nil , IP-10 Nil , MIP-1a Nil , and sIL-2Ra Nil and the antigen stimulated levels of IL-8 (Ag-Nil) , VEGF (Ag-Nil) , and MCP-3 (Ag-Nil) were potential biomarkers for differentiating between active TB and LTBI, with AUCs of 0.8, 0.86, 0.755, 0.845, 0.825, 0.812 and 0.75, respectively. The G-CSF (Ag-Nil) , GM-CSF (Ag-Nil) , IL-1a (Ag-Nil) , IL-2 (Ag-Nil) , IP-10 (Ag-Nil) , BCA-1 (Ag-Nil) and Eotaxin-1 (Ag-Nil) responses were significantly higher in patients with active TB and LTBI compared with healthy participants (p < 0.05), with AUCs of 0.922, 0.902, 0.908, 1.0, 0.937, 0.919 and 0.935, respectively. Our preliminary data suggest that unstimulated or stimulated levels of cytokines and chemokines could be used as host biomarkers for diagnosing active TB as well as additional biomarkers, except IFN-γ, for MTB infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bibliometric analysis of worldwide publications on multi-, extensively, and totally drug - resistant tuberculosis (2006-2015).

PubMed

Sweileh, Waleed M; AbuTaha, Adham S; Sawalha, Ansam F; Al-Khalil, Suleiman; Al-Jabi, Samah W; Zyoud, Sa'ed H

2016-01-01

The year 2015 marked the end of United Nations Millennium Development Goals which was aimed at halting and reversing worldwide tuberculosis (TB). The emergence of drug resistance is a major challenge for worldwide TB control. The aim of this study was to give a bibliometric overview of publications on multi-, extensively, and totally drug-resistant TB. Scopus database was used to retrieve articles on multidrug resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) tuberculosis for the study period (2006-2015). The number of publications, top productive countries and institutions, citation analysis, co-authorships, international collaboration, active authors, and active journals were retrieved and analyzed. A total of 2260 journal articles were retrieved. The mean ± SD citations per article was 7.04 ± 16.0. The h -index of retrieved data was 76. The number of publications showed a three - fold increase over the study period compared with less than two - fold increase in tuberculosis research during the same study period. Stratified by number of publications, the United States of America ranked first while Switzerland ranked first in productivity per 100 million people, and South Africa ranked first in productivity stratified per one trillion Gross Domestic Product. Three of the High Burden Countries (HBC) MDR-TB (India, China, and South Africa) were present in top productive countries. High percentage of international collaboration was seen among most HBC MDR-TB. Except for Plos One journal, most active journals in publishing articles on MDR, XDR, TDR-TB were in infection - related fields and in general medicine. Top 20 cited articles were published in prestigious journal such as Lancet and New England Journal of Medicine . The themes in top 20 cited articles were diverse, ranging from molecular biology, diagnostic tools, co-infection with HIV, and results of new anti-TB drugs. Publications on MDR, XDR and TDR - TB are increasing in the past decade. International collaboration was common. Many low resourced African and Asian countries will benefit from research leading to new diagnostic and screening technology of TB. The exchange of expertise, ideas and technology is of paramount importance in this field.

Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study.

PubMed

Walker, Naomi F; Wilkinson, Katalin A; Meintjes, Graeme; Tezera, Liku B; Goliath, Rene; Peyper, Janique M; Tadokera, Rebecca; Opondo, Charles; Coussens, Anna K; Wilkinson, Robert J; Friedland, Jon S; Elkington, Paul T

2017-07-01

Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation. MMP activity differed between HIV-1-infected and -uninfected TB patients and corresponded with specific TB clinical phenotypes. HIV-1-infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation, but increased plasma PIIINP, compared to HIV-1-uninfected TB patients. Elevated extrapulmonary extracellular matrix turnover was associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil derived and M. tuberculosis-antigen driven. Mycobacterium tuberculosis-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in vitro. MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrix turnover in HIV-1-infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibition is a potential host-directed therapy strategy for prevention and treatment of TB-IRIS. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

The epidemiology of childhood tuberculosis in the Netherlands: still room for prevention

PubMed Central

2014-01-01

Background The occurrence of tuberculosis (TB) among children has long been neglected as a public health concern. However, any child with TB is a sentinel event indicating recent transmission. Vaccination, early case finding and treatment of those latently infected with TB can prevent cases, severe morbidity and unnecessary death. Method The objective of the study was to describe the occurrence of TB events among children in the Netherlands which may be avoided through preventive measures. For this purpose we performed a trend analysis of routine Dutch TB and LTBI (surveillance data in 1993–2012 and a descriptive analysis of children with TB and with LTBI diagnosed in 2005–2012). Results Overall childhood TB incidence has declined over the last two decades from 3.6 in 1993 to 1.9 per 100,000 children in 2012. The decline was stronger among Dutch-born children compared to foreign-born children. In 2005–2012 64% of childhood TB cases were detected through active case finding. Foreign-born children with TB were less likely to be detected through active case finding, when not detected through post-entry TB screening. Childhood TB diagnosis was culture confirmed in 68% of passively detected cases and 12% of actively detected cases. Of 1,049 children with LTBI started on preventive treatment in 2005–2012, 90% completed treatment. In 37% of all childhood TB cases there was at least one ‘missed opportunity’ for prevention. Thirty nine percent of child TB patients eligible for BCG were not vaccinated. Conclusion Children with TB in the Netherlands are generally detected at an early stage and treatment completion rates are high. However, more TB cases among children can be prevented through enhancing TB case finding and screening and preventive treatment of latent TB infection among migrant children, and improving the coverage of BCG vaccination among eligible risk groups. PMID:24885314

Disruption of key NADH-binding pocket residues of the Mycobacterium tuberculosis InhA affects DD-CoA binding ability.

PubMed

Shaw, Daniel J; Robb, Kirsty; Vetter, Beatrice V; Tong, Madeline; Molle, Virginie; Hunt, Neil T; Hoskisson, Paul A

2017-07-05

Tuberculosis (TB) is a global health problem that affects over 10 million people. There is an urgent need to develop novel antimicrobial therapies to combat TB. To achieve this, a thorough understanding of key validated drug targets is required. The enoyl reductase InhA, responsible for synthesis of essential mycolic acids in the mycobacterial cell wall, is the target for the frontline anti-TB drug isoniazid. To better understand the activity of this protein a series of mutants, targeted to the NADH co-factor binding pocket were created. Residues P193 and W222 comprise a series of hydrophobic residues surrounding the cofactor binding site and mutation of both residues negatively affect InhA function. Construction of an M155A mutant of InhA results in increased affinity for NADH and DD-CoA turnover but with a reduction in V max for DD-CoA, impairing overall activity. This suggests that NADH-binding geometry of InhA likely permits long-range interactions between residues in the NADH-binding pocket to facilitate substrate turnover in the DD-CoA binding region of the protein. Understanding the precise details of substrate binding and turnover in InhA and how this may affect protein-protein interactions may facilitate the development of improved inhibitors enabling the development of novel anti-TB drugs.

Mining and Risk of Tuberculosis in Sub-Saharan Africa

PubMed Central

Basu, Sanjay; McKee, Martin; Lurie, Mark

2011-01-01

Objectives. We estimated the relationship between mining and tuberculosis (TB) among countries in sub-Saharan Africa. Methods. We used multivariate regression to estimate the contribution of mining activity to TB incidence, prevalence, and mortality, as well as rates of TB among people living with HIV, with control for economic, health system, and population confounders. Results. Mining production was associated with higher population TB incidence rates (adjusted b = 0.093; 95% confidence interval [CI] = 0.067, 0.120; with an increase of mining production of 1 SD corresponding to about 33% higher TB incidence or 760 000 more incident cases), after adjustment for economic and population controls. Similar results were observed for TB prevalence and mortality, as well as with alternative measures of mining activity. Independent of HIV, there were significant associations between mining production and TB incidence in countries with high HIV prevalence (≥ 4% antenatal HIV prevalence; HIV-adjusted B = 0.066; 95% CI = 0.050, 0.082) and between log gold mining production and TB incidence in all studied countries (HIV-adjusted B = 0.053; 95% CI = 0.032, 0.073). Conclusions. Mining is a significant determinant of countrywide variation in TB among sub-Saharan African nations. Comprehensive TB control strategies should explicitly address the role of mining activity and environments in the epidemic. PMID:20516372

Mining and risk of tuberculosis in sub-Saharan Africa.

PubMed

Stuckler, David; Basu, Sanjay; McKee, Martin; Lurie, Mark

2011-03-01

We estimated the relationship between mining and tuberculosis (TB) among countries in sub-Saharan Africa. We used multivariate regression to estimate the contribution of mining activity to TB incidence, prevalence, and mortality, as well as rates of TB among people living with HIV, with control for economic, health system, and population confounders. Mining production was associated with higher population TB incidence rates (adjusted b = 0.093; 95% confidence interval [CI] = 0.067, 0.120; with an increase of mining production of 1 SD corresponding to about 33% higher TB incidence or 760,000 more incident cases), after adjustment for economic and population controls. Similar results were observed for TB prevalence and mortality, as well as with alternative measures of mining activity. Independent of HIV, there were significant associations between mining production and TB incidence in countries with high HIV prevalence (≥ 4% antenatal HIV prevalence; HIV-adjusted B = 0.066; 95% CI = 0.050, 0.082) and between log gold mining production and TB incidence in all studied countries (HIV-adjusted B = 0.053; 95% CI = 0.032, 0.073). Mining is a significant determinant of countrywide variation in TB among sub-Saharan African nations. Comprehensive TB control strategies should explicitly address the role of mining activity and environments in the epidemic.

Knowledge and attitude of key community members towards tuberculosis: mixed method study from BRAC TB control areas in Bangladesh.

PubMed

Paul, Sukanta; Akter, Rahima; Aftab, Afzal; Khan, Antora M; Barua, Mrittika; Islam, Shayla; Islam, Akramul; Husain, Ashaque; Sarker, Malabika

2015-01-31

Bangladesh National Tuberculosis (TB) Control Programme adopted a number of strategies to facilitate TB diagnosis and treatment. 'Advocacy, Communication and Social Mobilization' (ACSM) was one of the key strategies implemented by BRAC (Bangladesh Rural Advancement Committee, a non-governmental development organization) TB control program. The purpose of this study is to assess the knowledge and attitudes of the key community members (KCMs) participated in ACSM in BRAC TB control areas. This study combined quantitative and qualitative methods using a mixed method approach. KCMs in three districts with low TB case detection rates were targeted to assess the ACSM program. The quantitative survey using a multi-stage random-sampling strategy was conducted among 432 participants. The qualitative study included in-depth interviews (IDIs) of a sub sample of 48 respondents. For quantitative analysis, descriptive statistics were reported using frequencies, percentages, and Chi square tests, while thematic analysis was used for qualitative part. Most (99%) of the participants had heard about TB, and almost all knew that TB is a contagious yet curable disease. More than half (53%) of the KCMs had good knowledge regarding TB, but BRAC workers were found to be more knowledgeable compared to other KCMs. However, considerable knowledge gaps were observed among BRAC community health workers. Qualitative results revealed that the majority of the KCMs were aware about the signs, symptoms and transmission pathways of TB and believed that smoking and addiction were the prime causes of transmission of TB. The knowledge about child TB was poor even among BRAC health workers. Stigma associated with TB was not uncommon. Almost all respondents expressed that young girls diagnosed with TB. This study finding has revealed varying levels of knowledge and mixed attitudes about TB among the KCMs. It also provides insight on the poor knowledge regarding child TB and indicate that despite the significant success of the TB program stigma is yet prevalent in the community. Future ACSM activities should engage community members against stigma and promote child TB related information for further improvement of BRAC TB Control Programme.

The Immune Interaction between HIV-1 Infection and Mycobacterium tuberculosis.

PubMed

Du Bruyn, Elsa; Wilkinson, Robert John

2016-12-01

The modulation of tuberculosis (TB)-induced immunopathology caused by human immunodeficiency virus (HIV)-1 coinfection remains incompletely understood but underlies the change seen in the natural history, presentation, and prognosis of TB in such patients. The deleterious combination of these two pathogens has been dubbed a "deadly syndemic," with each favoring the replication of the other and thereby contributing to accelerated disease morbidity and mortality. HIV-1 is the best-recognized risk factor for the development of active TB and accounts for 13% of cases globally. The advent of combination antiretroviral therapy (ART) has considerably mitigated this risk. Rapid roll-out of ART globally and the recent recommendation by the World Health Organization (WHO) to initiate ART for everyone living with HIV at any CD4 cell count should lead to further reductions in HIV-1-associated TB incidence because susceptibility to TB is inversely proportional to CD4 count. However, it is important to note that even after successful ART, patients with HIV-1 are still at increased risk for TB. Indeed, in settings of high TB incidence, the occurrence of TB often remains the first presentation of, and thereby the entry into, HIV care. As advantageous as ART-induced immune recovery is, it may also give rise to immunopathology, especially in the lower-CD4-count strata in the form of the immune reconstitution inflammatory syndrome. TB-immune reconstitution inflammatory syndrome will continue to impact the HIV-TB syndemic.

Trends in the epidemiology of childhood tuberculosis in Greece.

PubMed

Syridou, G; Mavrikou, M; Amanatidou, V; Spyridis, N; Prasad, P; Papaventsis, D; Kanavaki, S; Zaoutis, Th; Tsolia, M N

2012-06-01

A hospital referral center for childhood tuberculosis (TB). To evaluate the epidemiological and clinical features of childhood TB in the Greater Athens area in the last decade. We retrospectively reviewed the medical records of patients aged <14 years treated for active TB between January 2000 and December 2009 at our pediatric TB clinic and compared the results with the patient turnover during the previous decade (1990-1999). Data concerning demographic and clinical characteristics were analyzed. A total of 321 children (median age 5.57 years, 157 males) with active TB were identified. About one third originated from areas where TB was previously recognized to be highly endemic. Twenty-three children (7%) had extra-pulmonary TB, and 61% of them originated from TB-endemic areas. Bacteriological confirmation was obtained in 40% of patients from whom specimens were obtained: 1 of 26 (3.8%) strains was multidrug-resistant. Most cases with drug-resistant Mycobacterium tuberculosis were noted among immigrant children. The average annual TB incidence was estimated at 5.37 per 100 000 for children aged <14 years in the Greater Athens area. Time trend analysis for the 20-year period revealed a significant reduction in the total number of TB cases (P = 0.002) and in TB among children from low-incidence countries (P < 0.0001). In our settings, active TB is decreasing among children of Greek origin; disease epidemiology and drug resistance is influenced by the increasing influx of immigrants from areas where the disease is highly prevalent.

Implementing Tuberculosis Close-contact Investigation in a Tertiary Hospital in Iran.

PubMed

Shamaei, Masoud; Esmaeili, Shahrbanoo; Marjani, Majid; Tabarsi, Payam

2018-01-01

Close contact investigation is the essential key in tuberculosis (TB) case finding and an effective strategy for TB control program within any society. In this prospective study, 1186 close family contacts of hospitalized TB patients (index) in a referral TB hospital in Tehran-Iran were passively studied. These people were studied to rollout TB infection and disease. Demographic characteristics, clinical and laboratory data of these individuals were reviewed and summarized for analysis. A total of 886 (74.4%) close-family contacts completed their investigation. The index TB patients of these individuals were sputum smear negative for acid-fast bacilli in 137 cases (11.6%) and the rest were smear positive. A total of 610 (68.8%) close-family contact ruled out for TB infection or disease (Group I). A total of 244 cases (27.5%) had latent TB infection (Group II) and active TB (Group III) was confirmed in 32 cases (3.6%). A significant difference was shown for female gender, signs and symptoms, family size, and positive radiological finding between Group I and Group II. The study of index parameter including positive sputum smear/culture did not reveal any significant difference, but positive cavitary lesion significantly more has seen in active TB group ( P = 0.004). This study emphasizes on sign and symptoms and radiological finding in TB contact investigation, where index parameters including positive smear/culture, does not implicate any priority. Although cavitary lesions in index patient have more accompanied by active TB, close contact study should include all of TB indexes. This investigation should include chest radiography for these individuals.

An intervention of active TB case finding among smokers attending routine primary care facilities in China: an exploratory study.

PubMed

Wei, Xiaolin; Zou, Guangyan; Chong, Marc Kc; Xu, Lin

2015-09-01

Smoking is an important risk factor of TB. However, no studies have been conducted to identify TB cases from smokers. We assessed the process and initial impact of active case finding among smokers at primary care facilities in a setting with high smoking rates and TB burden. A prospective quasi-experimental study was conducted in para-urban communities in Yunnan China between September 2013 and June 2014. Smokers attending primary care facilities in the intervention group were prescribed chest X-rays if they had diabetes or TB symptoms, or were elders or close contacts of TB patients. Those with X-rays suggestive of TB were referred to TB dispensaries for diagnosis. Passive case finding was practiced in the control group. In the intervention group, we screened 471 smokers with high risks of TB, of whom 73% took chest X-ray examinations. Eight TB cases were diagnosed, reflecting a 1.7% yield rate of all screened smokers. Smokers with diabetes (OR 6.003, 95% CI 1.057-34.075) were more likely to have TB compared with those without. In total, the intervention group reported significantly higher TB notification rate compared with the control group (38.6 vs 22.9 per 100 000, p=0.016). Active case finding among smokers with high risks of TB was feasible and contributed to improved notification rates. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Scale-up of collaborative TB/HIV activities in Guyana.

PubMed

Baker, Brian J; Peterson, Brandy; Mohanlall, Jeetendra; Singh, Shanti; Hicks, Collene; Jacobs, Ruth; Ramos, Ruth; Allen, Barbara; Pevzner, Eric

2017-04-20

To assess scale-up of recommended tuberculosis (TB)/HIV activities in Guyana and to identify specific strategies for further expansion. Medical records and clinic registers were reviewed at nine TB clinics and 10 HIV clinics. At TB clinics, data were collected on HIV testing and antiretroviral therapy (ART) for patients with TB/HIV; at HIV clinics, data were collected on intensified case finding (ICF), tuberculin skin test (TST) results, and provision of isoniazid preventive therapy (IPT). At TB clinics, among 461 patients newly diagnosed with TB, 419 (90.9%) had a known HIV status and 121 (28.9%) were HIV-infected. Among the 63 patients with TB/HIV, 33 (52.4%) received ART. Among the 45 patients with TB/HIV for whom dates of HIV diagnosis were available, 38 (84.4%) individuals knew their HIV status prior to TB diagnosis. At HIV clinics, among 127 patients eligible to receive a TST, 87 (68.5%) received a TST, 66 (75.9%) had a TST result, seven (10.6%) had a newly positive result, two had a previously positive result, and six of nine patients with positive results (66.7%) received IPT. ICF could not be assessed because of incomplete or discrepant documentation. An in-depth evaluation of TB/HIV activities successfully identified areas of success and remaining challenges. At TB clinics, HIV testing rates are high; further scale-up of ART for persons with TB/HIV is needed. At HIV clinics, use of TST to focus IPT is a feasible and efficient strategy; improving rates of annual TST screening will allow for further expansion of IPT.

Screening for tuberculosis in an urban shelter for homeless in Switzerland: a prospective study.

PubMed

Janssens, Jean-Paul; Wuillemin, Timothee; Adler, Dan; Jackson, Yves

2017-05-16

Whereas high risk groups such as asylum seekers are systematically screened for active tuberculosis (TB) upon entry in Switzerland, this strategy does not apply to homeless persons despite a reported high risk. Geneva health and social authorities implemented an intersectoral project to screen for active TB in homeless persons. We aimed to assess acceptability of this program and prevalence of active TB in this group. This prospective study targeted all homeless adults registering for shelter accommodation in Geneva during winter 2015. Applicants were proposed a questionnaire-based screening ( www.tb-screen.ch ) exploring epidemiological and clinical risk factors for active TB. Participants with a positive score underwent diagnostic procedures at Geneva University Hospital. Enhanced TB surveillance targeting homeless persons in the community was continued 3 months after the study termination. Overall, 726/832 (87.3%) homeless persons accepted the screening procedure. Most were young male migrants without access to care in Switzerland. Male gender (adjusted OR: 2.14; 95% confidence interval: 1.27-3.62), age below 25 years (aOR: 4.16; 95% CI: 1.27-13.64) and short duration of homelessness (aOR: 1.75; 95% CI: 1.06-2.87) were predictors of acceptance. Thirty (4.1%) had positive screening scores but none of the 24 who underwent further testing had active TB. Post-study surveillance did not identify any incident case in Geneva. Active TB screening targeting highly mobile homeless persons in shelters was well accepted and feasible. The participants' sociodemographic profile highlighted the heterogeneity of homeless groups in Europe and the null TB prevalence the variability of their active TB risks. These findings underline the feasibility of health programs targeting this hard to reach group and the need for close monitoring of this social group considering the rapid changes in international mobility patterns to tailor preventive and screening strategies to the local context.

Tuberculosis in recipients of solid-organ transplants during 1995-2015 in Cali, Colombia.

PubMed

García-Goez, J F; Munera, G A; Rojas, V; Pacheco, R; Caylá, J A; Miro, J M

2017-11-01

Tuberculosis (TB) in solid-organ transplants (SOTs) is an important opportunistic infection associated with mortality and graft loss. SOT recipients carry a higher risk of contracting active TB than the general population. Clinical and radiographic presentations are non-specific, and sputum smear and culture have low yields. TB patients with SOTs require standard anti-tuberculosis treatment. However, rifampicin (RMP) use is associated with a 30% rate of acute graft rejection (AGR) and a 20% rate of transplant loss. To determine treatment outcomes in SOT recipients with active TB. A retrospective study of clinical and microbiological data and TB treatment outcomes. Among the 2349 transplants assessed, active TB was detected in 31 recipients; 55% had pulmonary TB and 40% were sputum smear-positive. In 32% of the patients, TB was diagnosed 30 days after symptom onset, 77% of the patients were cured and 10% died. AGR occurred in 13%. TB was diagnosed in <30 days. Anti-tuberculosis treatment without RMP (80% vs. 67%; P = 0.48, OR 0.5, 95%CI 0.07-3.55) and with moxifloxacin yielded higher treatment success rates and a lower risk of AGR.

Type-1 polarised dendritic cells are a potent immunogen against Mycobacterium tuberculosis.

PubMed

Satake, Y; Nakamura, Y; Kono, M; Hozumi, H; Nagata, T; Tsujimura, K; Enomoto, N; Fujisawa, T; Inui, N; Fujiyama, T; Tokura, Y; Matsui, T; Yokomura, K; Shirai, M; Hayakawa, H; Suda, T

2017-05-01

Application of immunotherapy using dendritic cells (DCs) is considered an effective treatment strategy against persistent Mycobacterium tuberculosis infection. With the goal of developing improved therapeutic vaccination strategies for patients with tuberculosis (TB), we tested the ability of ex vivo-generated DCs to induce an effective TB antigen-specific type-1 immune response. Monocyte-derived DCs from TB patients were induced to mature using a 'standard' cytokine cocktail (interleukin [IL] 1β, tumour necrosis factor alpha [TNF-α], IL-6 and prostaglandin E2) or a type 1-polarised DC (DC1) cocktail (IL-1β, TNF-α, interferon [IFN] α, IFN-γ and polyinosinic:polycytidylic acid), and were loaded with the established TB antigen 6-kDa early secretory antigenic target protein (ESAT-6). Although DC1s from TB patients expressed the same levels of multiple co-stimulatory molecules (CD83, CD86, CD80 and CD40) as the standard DCs (sDCs), DC1s secreted substantially higher levels of IL-12p70. Furthermore, when DCs pulsed with or without ESAT-6 were cultured with lymphocytes from the same patients, DC1s induced much higher numbers of ESAT-6-specific IFN-γ-producing T-cells than sDCs, as manifested by their superior induction of natural killer cell activation and antigen-independent suppression of regulatory T-cells. TB antigen-loaded DC1s are potent inducers of antigen-specific T-cells, which could be used to develop improved immunotherapies of TB.

Performance of a lateral flow immunochromatography test for the rapid diagnosis of active tuberculosis in a large multicentre study in areas with different clinical settings and tuberculosis exposure levels.

PubMed

Manga, Selene; Perales, Rocio; Reaño, Maria; D'Ambrosio, Lia; Migliori, Giovanni Battista; Amicosante, Massimo

2016-11-01

Tuberculosis (TB) continues to cause an outsized burden of morbidity and mortality worldwide, still missing efficient and largely accessible diagnostic tools determining an appropriate control of the disease. Serological tests have the potentially to impact TB diagnosis, in particular in extreme clinical settings. The diagnostic performances of the TB-XT HEMA EXPRESS (HEMA-EXPRESS) immunochromatographic rapid test for active TB diagnosis, based on use of multiple Mycobacterium tuberculosis (MTB) specific antigens, have been evaluated in a large study multicentre TB case-finding study, in populations with different exposure level to TB. A total of 1,386 subjects were enrolled in the six participating centres in Peru: 290 active-TB and 1,096 unaffected subjects. The TB prevalence (overall 20.5%) varied between 4.0% and 41.1% in the different study groups. Overall, the HEMA-EXPRESS test had 30.6% sensitivity (range 3.9-77.9%) and 84.6% specificity (range 51.6-97.3%). A significant inverse correlation between test accuracy (overall 73.5%, range 40.4-96.4%) and TB prevalence in the various study populations was observed (Pearson's r=-0.7985; P=0.05). HEMA-EXPRESS, is rapid and relatively inexpensive test suitable for routine use in TB diagnosis. In low TB prevalence conditions, test performance appears in line with WHO Target Product Profile for TB diagnostics. Performances appear suboptimal in high TB prevalence settings. Appropriate set-up in operative clinical settings has to be considered for novel serological tests for TB diagnosis, particularly for formats suitable for point-of-care use.

Tuberculosis Notification by Private Sector' Physicians in Tehran.

PubMed

Ahmadi, Ayat; Nedjat, Saharnaz; Gholami, Jaleh; Majdzadeh, Reza

2015-01-01

A small proportion of physicians adhere to tuberculosis (TB) notification regulations, particularly in the private sector. In most developing countries, the private sector has dominance over delivering services in big cities. In such circumstances deviation from the TB treatment protocol is frequently happening. This study sought to estimate TB notification in the private sector and settle on determinants of TB notification by private sector physicians. A population-based study has been conducted; private physicians at their clinics were interviewed. The total number of 443 private sectors' physicians has been chosen by the stratified random sampling method. Appropriate descriptive analysis was used to describe the study's participants. Logistic regression was used for bivariable and multivariable analysis. The response rate of the study was 90.06 (399%). Among responders, who had stated that they were suspicious of TB over the recent year, 62 (16.45%) stated that they reported cases of TB at least once during the same period. Having reporting requirements and the number of visited patients was significantly related to TB suspicious (odds ratio = 2.84, confidence interval: 1.62-5, P < 0.01). Workplace and access to relevant resources are associated with TB notification (P < 0.05). In poor resource settings with a high burden of TB, the public health administration can promote notification activities in the private sector by simple and quick interventions. It seems that a considerable fraction of private sector physicians, not all of them, will notify TB if they are provided with primary information and primary resources. To optimize the TB notification, however, intersectoral interventions are more likely to be successful.

Epidemics. War on an old scourge. Tuberculosis is back and some nations are unable to restrain it.

PubMed

1995-09-29

The World Health Organization (WHO) in 1993 declared a global emergency against tuberculosis (TB). Despite that call for action and government programs to slow its spread, TB continues to kill millions of people annually. An estimated 20 million people are sick worldwide with full-blown TB, nearly two-thirds of whom are in Asia. TB bacteria are emitted from infectious individuals through a cough, sneeze, or breathy discourse, after which they travel through the air to infect other individuals. If untreated, there is a 5-10% chance that the bacteria will become active, attacking the lungs, causing prolonged coughing, weight loss, and ultimately death. Living in crowded or unclean areas increases one's risk of contracting the TB bacteria. Once infected, compromised immune systems will have a harder time than healthy, strong systems fighting off development of the disease. The poor are therefore usually the most severely affected by TB. HIV infection and disease also increase one's susceptibility to TB and other diseases, in addition to making TB more difficult to detect. HIV is spreading in Asia faster than anywhere else on the planet. Since the source of the current TB epidemic is infectious patients who are not totally cured, the WHO recommends that health care workers provide patients with a proper dose of antibiotics and make sure that they take it every day for six months as the most effective TB control strategy. China, India, and Thailand, Asia's most seriously affected countries for TB, have committed to adopting the strategy.

Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation

PubMed Central

2012-01-01

Background Transient receptor potential cation channel subfamily M member 8 (TRPM8) is activated by cold temperature in vitro and has been demonstrated to act as a ‘cold temperature sensor’ in vivo. Although it is known that agonists of this ‘cold temperature sensor’, such as menthol and icilin, cause a transient increase in body temperature (Tb), it is not known if TRPM8 plays a role in Tb regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in Tb regulation. Results We characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496) as potent and selective antagonists of TRPM8 and tested their effects on Tb in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in Tb (maximum decrease of 0.98°C). Since thermoregulation is a homeostatic process that maintains Tb about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in Tb. Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the Tb decrease Day 2 onwards. Conclusions The data reported here demonstrate that TRPM8 channels play a role in Tb regulation. Further, a reduction of magnitude in Tb decrease after repeated dosing of an antagonist suggests that TRPM8’s role in Tb maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics. PMID:22571355

Radiation-induced luminescence properties of Tb-doped Li3PO4-B2O3 glasses

NASA Astrophysics Data System (ADS)

Isokawa, Yuya; Hirano, Shotaro; Kawano, Naoki; Okada, Go; Kawaguchi, Noriaki; Yanagida, Takayuki

2018-02-01

In this study, we developed Li3PO4-B2O3 glasses doped with different concentrations of Tb (0.1, 0.3, 1.0, 3.0, and 10.0%) as well as undoped glass, and then the prepared glasses were studied for the optical, dosimeter and scintillator properties. The Tb-doped samples indicated radioluminescence and photoluminescence (PL) due to the 4f-4f transitions of Tb3+ with sharp spectral features peaking around 375, 410, 435, 480, 540, 590 and 620 nm. The luminescence decay times of radioluminescence and PL were 2.3-2.7 ms and 2.7-2.9 ms, respectively. The shorter radioluminescence decay time than that of PL indicated quenching effect of excited states in radioluminescence. As the concentration of Tb increased, both the radioluminescence intensity and PL quantum yield (QY) increased, and the 10.0% Tb-doped sample showed the highest radioluminescence intensity and QY (54.3%). In addition, thermally-stimulated luminescence (TSL) was observed after irradiating with X-rays. The sensitivity was the highest for the 3.0% Tb-doped sample having a dynamic range from 0.1 mGy to 10 Gy, which was equivalent to commercial dosimeters. The comprehensive studies suggested that X-ray generated charges are captured at TSL-active centers more effectively at lower concentrations of Tb whereas the recombination probability at Tb center during irradiation increases with the concentration of Tb. Consequently, the optimal Tb concentration was 10% as scintillator and 3.0% for TSL dosimeter, among the present samples.

Genetic contribution of CISH promoter polymorphisms to susceptibility to tuberculosis in Chinese children.

PubMed

Sun, Lin; Jin, Ya-qiong; Shen, Chen; Qi, Hui; Chu, Ping; Yin, Qing-qin; Li, Jie-qiong; Tian, Jian-ling; Jiao, Wei-wei; Xiao, Jing; Shen, A-dong

2014-01-01

Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide, particularly in developing countries. A series of candidate genes have been suggested to be associated with development of TB disease. Among them, the human Cytokine-inducible Src homology 2(SH2) domain protein (CISH) gene has been very recently reported to be involved in T cell activation and differentiation in response to Mycobacterium tuberculosis infection. Here, we studied the association between CISH promoter polymorphisms and pediatric TB. A case-control study enrolled 352 TB patients and 527 healthy controls, who were of Han Chinese ethnicity and aged from 0.2 to 18 years. CISH gene promoter SNPs rs414171, rs622502 and rs809451 were genotyped in all subjects and transcriptional activity, mRNA level, and plasma cytokine level of subjects with different genotypes were further examined. Carriers with rs414171TT homozygotes and rs809451GC heterozygotes had a 1.78-fold (95% CI,1.16-2.74) and 1.86-fold (95% CI, 1.26-2.74) excess risk of developing TB compared to those with wild-type genotypes. A greater risk of TB disease was observed in population carrying C(-809451)-T(-414171)-C(-622502) haplotype (OR 3.66, 95% CI:2.12-6.32). The G(-809451)-A(-414171)-C(-622502)-containing CISH promoter drove a 5.43-fold increased reporter expression compared to the C(-809451)-T(-414171)-C(-622502)-containing counterpart in Hela cell lines (P = 0.0009). PBMCs carrying rs414171TT homozygotes and rs809451GC heterozygotes showed a reduced CISH mRNA level compared to cells carrying wild type genotypes. Individuals with the rs414171TT genotype had significantly increased IL-12p40 and IL-10 production. In conclusion, CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis.

Monocarbonyl analogs of curcumin inhibit growth of antibiotic sensitive and resistant strains of Mycobacterium tuberculosis

PubMed Central

Baldwin, Patrick R.; Reeves, Analise Z.; Powell, Kimberly R.; Napier, Ruth J.; Swimm, Alyson I.; Sun, Aiming; Giesler, Kyle; Bommarius, Bettina; Shinnick, Thomas M.; Snyder, James P.; Liotta, Dennis C.; Kalman, Daniel

2016-01-01

Tuberculosis (TB) is a major public health concern worldwide with over 2 billion people currently infected. The rise of strains of Mycobacterium tuberculosis (Mtb) that are resistant to some or all first and second line antibiotics, including multidrug-resistant (MDR), extensively drug resistant (XDR) and totally drug resistant (TDR) strains, is of particular concern and new anti-TB drugs are urgently needed. Curcumin, a natural product used in traditional medicine in India, exhibits anti-microbial activity that includes Mtb, however it is relatively unstable and suffers from poor bioavailability. To improve activity and bioavailability, mono-carbonyl analogs of curcumin were synthesized and screened for their capacity to inhibit the growth of Mtb and the related Mycobacterium marinum (Mm). Using disk diffusion and liquid culture assays, we found several analogs that inhibit in vitro growth of Mm and Mtb, including rifampicin-resistant strains. Structure activity analysis of the analogs indicated that Michael acceptor properties are critical for inhibitory activity. However, no synergistic effects were evident between the monocarbonyl analogs and rifampicin on inhibiting growth. Together, these data provide a structural basis for the development of analogs of curcumin with pronounced anti-mycobacterial activity and provide a roadmap to develop additional structural analogs that exhibit more favorable interactions with other anti-TB drugs. PMID:25618016

Ten years' experience of Directly Observed Treatment Short-course (DOTS) in Gambella Regional State, Ethiopia: An evaluation of tuberculosis control program.

PubMed

Sisay, Solomon; Mengistu, Belete; Erku, Woldargay; Woldeyohannes, Desalegne

2016-12-01

World Health Organization (WHO) declared tuberculosis (TB) as a global public health emergency and recommended DOTS as a standard strategy for controlling the disease. TB is one of the major causes of infectious diseases in the world, and 25% of all avoidable deaths in developing countries. About a third of the world's population is estimated to be infected with tubercle bacilli, and hence at risk of developing active disease. The objective of the study was, therefore, to evaluate the impact of DOTS strategy on smear-positive pulmonary tuberculosis case finding and their treatment outcomes in Gambella Regional State, Ethiopia. A retrospective health facility-based descriptive study was employed. Quarterly data were collected by using WHO structured reporting format for TB case finding and treatment outcome from all DOTS implementing health facilities in the region. A total of 10,024 TB cases (all forms) were registered and reported between the periods from 2003 up to 2012. Out of these, 4100 (40.9%) were smear-positive pulmonary TB, 3164 (31.6%) were smear-negative pulmonary TB and 2760 (27.5%) had extra-pulmonary TB. An average case detection rate (CDR) 1 of 40.9% (SD=0.1) and treatment success rate (TSR) 2 of 55.7% (SD=0.28) for smear-positive pulmonary TB including other forms of TB were reported for the specified years period. Additionally, the average mean values of treatment defaulter and treatment failure rates were 4.2% and 0.3%, respectively. The recommended TSR set by WHO was achieved as it was already been fulfilled more than 85% from 2009 up to 2011 in the region and the reported CDR was far below (40.9%) for smear-positive pulmonary TB including other forms of TB from the target. Therefore, extensive efforts should be established to maintain the achieved TSR and to increase the low level of CDR for all forms of TB cases through implementing alternative case finding strategies. Copyright © 2016.

Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon γ release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial.

PubMed

Ruhwald, Morten; Aggerbeck, Henrik; Gallardo, Rafael Vázquez; Hoff, Søren T; Villate, José I; Borregaard, Bettine; Martinez, José A; Kromann, Ingrid; Penas, Antón; Anibarro, Luis L; de Souza-Galvão, Maria Luiza; Sánchez, Francisca; Rodrigo-Pendás, Jose Ángel; Noguera-Julian, Antoni; Martínez-Lacasa, Xavier; Tuñez, Maria Victoria; Fernández, Virginia Leiro; Millet, Joan P; Moreno, Antonio; Cobos, Nazaret; Miró, José M; Roldan, Llanos; Orcau, Angels; Andersen, Peter; Caylá, Joan A

2017-04-01

Targeted screening and treatment of Mycobacterium tuberculosis infection substantially reduces the risk of developing active tuberculosis. C-Tb (Statens Serum Institute, Copenhagen, Denmark) is a novel specific skin test based on ESAT-6 and CFP10 antigens. We investigated the safety and diagnostic potential of C-Tb compared with established tests in the contact-tracing setting. Negative controls, close contacts, occasional contacts, and patients with active pulmonary tuberculosis were enrolled at 13 centres in Spain. We compared C-Tb with the QuantiFERON-TB Gold In-Tube ([QFT] Qiagen, Hilden, Germany) interferon γ release assay (IGRA) and the purified protein derivative (PPD) RT 23 tuberculin skin test ([TST] Statens Serum Institute). All participants older than 5 years were tested with QFT. Some participants in the negative control group received C-Tb without the TST to test for potential interactions between C-Tb and PPD RT 23. The rest were randomly assigned in blocks of ten and tested with both C-Tb and TST, with five in each block receiving injection of C-Tb in the right arm and the TST in the left arm and five vice versa. The primary and safety analyses were done in all participants randomly assigned to a group who received any test. This trial is registered with ClinicalTrials.gov, number NCT01631266, and with EudraCT, number 2011-005617-36. From July 24, 2012, to Oct 2, 2014, 979 participants were enrolled, of whom 263 were negative controls, 299 were occasional contacts, 316 were close contacts, and 101 were patients with tuberculosis. 970 (99%) participants completed the trial. Induration sizes were similar for C-Tb and TST, but TST positivity was affected by BCG vaccination status. We found a strong positive trend towards C-Tb test positivity with increasing risk of infection, from 3% in negative controls to 16% in occasional contacts, to 43% in close contacts. C-Tb and QFT results were concordant in 785 (94%) of 834 participants aged 5 years and older, and results did not differ significantly between exposure groups. The safety profile of C-Tb was similar to that for the TST. C-Tb delivered IGRA-like results in a field-friendly format. Being unaffected by BCG vaccination status, the C-Tb skin test might provide more accurate treatment guidance in settings where the TST is commonly used. Statens Serum Institut. Copyright © 2017 Elsevier Ltd. All rights reserved.

Trends in, and factors associated with, HIV infection amongst tuberculosis patients in the era of anti-retroviral therapy: a retrospective study in England, Wales and Northern Ireland.

PubMed

Winter, Joanne R; Stagg, Helen R; Smith, Colette J; Lalor, Maeve K; Davidson, Jennifer A; Brown, Alison E; Brown, James; Zenner, Dominik; Lipman, Marc; Pozniak, Anton; Abubakar, Ibrahim; Delpech, Valerie

2018-06-07

HIV increases the progression of latent tuberculosis (TB) infection to active disease and contributed to increased TB in the UK until 2004. We describe temporal trends in HIV infection amongst patients with TB and identify factors associated with HIV infection. We used national surveillance data of all TB cases reported in England, Wales and Northern Ireland from 2000 to 2014 and determined HIV status through record linkage to national HIV surveillance. We used logistic regression to identify associations between HIV and demographic, clinical and social factors. There were 106,829 cases of TB in adults (≥ 15 years) reported from 2000 to 2014. The number and proportion of TB patients infected with HIV decreased from 543/6782 (8.0%) in 2004 to 205/6461 (3.2%) in 2014. The proportion of patients diagnosed with HIV > 91 days prior to their TB diagnosis increased from 33.5% in 2000 to 60.2% in 2013. HIV infection was highest in people of black African ethnicity from countries with high HIV prevalence (32.3%), patients who misused drugs (8.1%) and patients with miliary or meningeal TB (17.2%). There has been an overall decrease in TB-HIV co-infection and a decline in the proportion of patients diagnosed simultaneously with both infections. However, high rates of HIV remain in some sub-populations of patients with TB, particularly black Africans born in countries with high HIV prevalence and people with a history of drug misuse. Whilst the current policy of testing all patients diagnosed with TB for HIV infection is important in ensuring appropriate management of TB patients, many of these TB cases would be preventable if HIV could be diagnosed before TB develops. Improving screening for both latent TB and HIV and ensuring early treatment of HIV in these populations could help prevent these TB cases. British HIV Association guidelines on latent TB testing for people with HIV from sub-Saharan Africa remain relevant, and latent TB screening for people with HIV with a history of drug misuse, homelessness or imprisonment should also be considered.

Opportunities and Challenges for Natural Products as Novel Antituberculosis Agents.

PubMed

Farah, Shrouq I; Abdelrahman, Abd Almonem; North, E Jeffrey; Chauhan, Harsh

2016-01-01

Current tuberculosis (TB) treatment suffers from complexity of the dosage regimens, length of treatment, and toxicity risks. Many natural products have shown activity against drug-susceptible, drug-resistant, and latent/dormant Mycobacterium tuberculosis, the pathogen responsible for TB infections. Natural sources, including plants, fungi, and bacteria, provide a rich source of chemically diverse compounds equipped with unique pharmacological, pharmacokinetic, and pharmacodynamic properties. This review focuses on natural products as starting points for the discovery and development of novel anti-TB chemotherapy and classifies them based on their chemical nature. The classes discussed are divided into alkaloids, chalcones, flavonoids, peptides, polyketides, steroids, and terpenes. This review also highlights the importance of collaboration between phytochemistry, medicinal chemistry, and physical chemistry, which is very important for the development of these natural compounds.

Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer

PubMed Central

Nelson, Nadine; Szekeres, Karoly; Iclozan, Cristina; Rivera, Ivannie Ortiz; McGill, Andrew; Johnson, Gbemisola; Nwogu, Onyekachi

2017-01-01

Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros’ stability in our model. We also showed that this loss of Ikaros expression is associated with a significant decrease in CD4+ and CD8+ T cell percentages but increased CD4+CD25+ Tregs in TB mice. In this study, we evaluated the effects of the dietary flavonoid apigenin (API), on Ikaros expression and T cell immune responses. Treatment of splenocytes from naïve mice with (API) stabilized Ikaros expression and prevented Ikaros downregulation in the presence of murine Panc02 cells in vitro, similar to the proteasome inhibitor MG132. In vivo treatment of TB mice with apigenin (TB-API) improved survival, reduced tumor weights and prevented splenomegaly. API treatment also restored protein expression of some Ikaros isoforms, which may be attributed to its moderate inhibition of CK2 activity from splenocytes of TB-API mice. This partial restoration of Ikaros expression was accompanied by a significant increase in CD4+ and CD8+ T cell percentages and a reduction in Treg percentages in TB-API mice. In addition, CD8+ T cells from TB-API mice produced more IFN-γ and their splenocytes were better able to prime allogeneic CD8+ T cell responses compared to TB mice. These results provide further evidence that Ikaros is regulated by CK2 in our pancreatic cancer model. More importantly, our findings suggest that API may be a possible therapeutic agent for stabilizing Ikaros expression and function to maintain T cell homeostasis in murine PC. PMID:28152014

Active Tuberculosis among Homeless Persons, Toronto, Ontario, Canada, 1998–2007

PubMed Central

Rea, Elizabeth; McDermaid, Cameron; Stuart, Rebecca; Chambers, Catharine; Wang, Jun; Chan, Angie; Gardam, Michael; Jamieson, Frances; Yang, Jae; Hwang, Stephen W.

2011-01-01

While tuberculosis (TB) in Canadian cities is increasingly affecting foreign-born persons, homeless persons remain at high risk. To assess trends in TB, we studied all homeless persons in Toronto who had a diagnosis of active TB during 1998–2007. We compared Canada-born and foreign-born homeless persons and assessed changes over time. We identified 91 homeless persons with active TB; they typically had highly contagious, advanced disease, and 19% died within 12 months of diagnosis. The proportion of homeless persons who were foreign-born increased from 24% in 1998–2002 to 39% in 2003–2007. Among foreign-born homeless persons with TB, 56% of infections were caused by strains not known to circulate among homeless persons in Toronto. Only 2% of infections were resistant to first-line TB medications. The rise in foreign-born homeless persons with TB strains likely acquired overseas suggests that the risk for drug-resistant strains entering the homeless shelter system may be escalating. PMID:21392424

Blood transcriptomic diagnosis of pulmonary and extrapulmonary tuberculosis

PubMed Central

Roe, Jennifer K; Thomas, Niclas; Gil, Eliza; Best, Katharine; Tsaliki, Evdokia; Morris‑Jones, Stephen; Stafford, Sian; Simpson, Nandi; Witt, Karolina D; Chain, Benjamin; Miller, Robert F; Martineau, Adrian

2016-01-01

BACKGROUND. Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB. METHODS. Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection. RESULTS. We identified and validated elevated blood basic leucine zipper transcription factor 2 (BATF2) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1–negative individuals, and 0.85 in HIV-1–infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1. CONCLUSIONS. Elevated blood BATF2 transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever. FUNDING. MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR. PMID:27734027

Blood transcriptomic diagnosis of pulmonary and extrapulmonary tuberculosis.

PubMed

Roe, Jennifer K; Thomas, Niclas; Gil, Eliza; Best, Katharine; Tsaliki, Evdokia; Morris-Jones, Stephen; Stafford, Sian; Simpson, Nandi; Witt, Karolina D; Chain, Benjamin; Miller, Robert F; Martineau, Adrian; Noursadeghi, Mahdad

2016-10-06

BACKGROUND. Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB. METHODS. Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection. RESULTS. We identified and validated elevated blood basic leucine zipper transcription factor 2 ( BATF2 ) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1-negative individuals, and 0.85 in HIV-1-infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1. CONCLUSIONS. Elevated blood BATF2 transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever. FUNDING. MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR.

Anti-biofilm properties of the antimicrobial peptide temporin 1Tb and its ability, in combination with EDTA, to eradicate Staphylococcus epidermidis biofilms on silicone catheters.

PubMed

Maisetta, Giuseppantonio; Grassi, Lucia; Di Luca, Mariagrazia; Bombardelli, Silvia; Medici, Chiara; Brancatisano, Franca Lisa; Esin, Semih; Batoni, Giovanna

2016-08-01

In search of new antimicrobials with anti-biofilm potential, in the present study activity of the frog-skin derived antimicrobial peptide temporin 1Tb (TB) against Staphylococcus epidermidis biofilms was investigated. A striking ability of TB to kill both forming and mature S. epidermidis biofilms was observed, especially when the peptide was combined with cysteine or EDTA, respectively. Kinetics studies demonstrated that the combination TB/EDTA was active against mature biofilms already after 2-4-h exposure. A double 4-h exposure of biofilms to TB/EDTA further increased the therapeutic potential of the same combination. Of note, TB/EDTA was able to eradicate S. epidermidis biofilms formed in vitro on silicone catheters. At eradicating concentrations, TB/EDTA did not cause hemolysis of human erythrocytes. The results shed light on the anti-biofilm properties of TB and suggest a possible application of the peptide in the lock therapy of catheters infected with S. epidermidis.

Guidance for National Tuberculosis Programmes on the management of tuberculosis in children. Chapter 1: introduction and diagnosis of tuberculosis in children.

PubMed

2006-10-01

About one million children develop tuberculosis (TB) annually worldwide, accounting for about 11% of all TB cases. Children with TB differ from adults in their immunological and pathophysiological response in ways that may have important implications for the prevention, diagnosis and treatment of TB in children. There is an urgent need to improve the diagnosis and management of children with TB, and the prevention of TB in children, by ensuring their inclusion under the implementation of the Stop TB strategy by National TB Programmes. Critical areas for further research include a better understanding of the epidemiology of childhood TB, vaccine development, the development of better diagnostic techniques, new drug development, and the optimal formulations and dosing of first- and second-line TB drugs in children. Specifically regarding the diagnosis of TB in children, this relies on a careful and thorough assessment of all the evidence derived from a careful history, clinical examination and relevant investigations, e.g., tuberculin skin test, chest radiograph and sputum smear microscopy. Although bacteriological confirmation of TB is not always possible, it should be sought whenever possible, e.g., by sputum microscopy in children with suspected pulmonary TB who are old enough to produce a sputum sample. A trial of treatment with TB medications is not generally recommended as a method to diagnose TB in children. New, improved diagnostic tests are urgently needed.

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

PubMed Central

Walker, Naomi F.; Clark, Simon O.; Oni, Tolu; Andreu, Nuria; Tezera, Liku; Singh, Shivani; Saraiva, Luísa; Pedersen, Bernadette; Kelly, Dominic L.; Tree, Julia A.; D'Armiento, Jeanine M.; Meintjes, Graeme; Mauri, Francesco A.; Williams, Ann; Wilkinson, Robert J.; Friedland, Jon S.

2012-01-01

Rationale: Tuberculosis kills more than 1.5 million people per year, and standard treatment has remained unchanged for more than 30 years. Tuberculosis (TB) drives matrix metalloproteinase (MMP) activity to cause immunopathology. In advanced HIV infection, tissue destruction is reduced, but underlying mechanisms are poorly defined and no current antituberculous therapy reduces host tissue damage. Objectives: To investigate MMP activity in patients with TB with and without HIV coinfection and to determine the potential of doxycycline to inhibit MMPs and decrease pathology. Methods: Concentrations of MMPs and cytokines were analyzed by Luminex array in a prospectively recruited cohort of patients. Modulation of MMP secretion and Mycobacterium tuberculosis growth by doxycycline was studied in primary human cells and TB-infected guinea pigs. Measurements and Main Results: HIV coinfection decreased MMP concentrations in induced sputum of patients with TB. MMPs correlated with clinical markers of tissue damage, further implicating dysregulated protease activity in TB-driven pathology. In contrast, cytokine concentrations were no different. Doxycycline, a licensed MMP inhibitor, suppressed TB-dependent MMP-1 and -9 secretion from primary human macrophages and epithelial cells by inhibiting promoter activation. In the guinea pig model, doxycycline reduced lung TB colony forming units after 8 weeks in a dose-dependent manner compared with untreated animals, and in vitro doxycycline inhibited mycobacterial proliferation. Conclusions: HIV coinfection in patients with TB reduces concentrations of immunopathogenic MMPs. Doxycycline decreases MMP activity in a cellular model and suppresses mycobacterial growth in vitro and in guinea pigs. Adjunctive doxycycline therapy may reduce morbidity and mortality in TB. PMID:22345579

Antibacterial Activities of Endophytic Bacteria Isolated from Taxus brevifolia Against Foodborne Pathogenic Bacteria.

PubMed

Islam, Nurul; Choi, Jaehyuk; Baek, Kwang-Hyun

2018-05-01

Endophytes are a potential source of novel bioactive compounds with medicinal properties. In this study, 41 endophytic bacteria (EB) were isolated from tissues of a medicinally important plant Taxus brevifolia (Pacific yew). The objective was to screen all the EB isolates for their antibacterial effects against five foodborne pathogenic bacteria: Bacillus cereus ATCC10876, Staphylococcus aureus ATCC12600, Listeria monocytogenes ATCC19115, Escherichia coli ATCC43890, and Salmonella Typhimurium ATCC19585. Among the EB isolates, T. brevifolia seed (TbS)-8, T. brevifolia fleshy part of fruit (TbFl)-10, T. brevifolia leaf (TbL)-22, TbS-29, and TbL-34 exerted significant antibacterial activity against the tested foodborne pathogens. Especially TbFl-10 showed the highest antibacterial activity against all the tested bacteria and was identified as Paenibacillus kribbensis (Pk). Furthermore, an ethyl acetate extract of Pk-TbFl-10 possessed antibacterial activities against the tested five foodborne pathogenic bacteria, with zones of inhibition from 15.71 ± 2.85 to 13.01 ± 2.12 mm. Scanning electron microscopy analysis revealed ruptured, lysed, shrunk, and swollen cells of all the tested foodborne pathogens treated with the ethyl acetate extract of Pk-TbFl-10, suggesting that a metabolite(s) of Pk-TbFl-10 penetrates the cell membrane and causes cell lysis leading to cell death. Our results indicate that Pk-TbFl-10 isolated from T. brevifolia can serve as a novel source of natural antibacterial agents against foodborne pathogenic bacteria, with potential applications in the pharmaceutical industry.

Mathematical modeling of transmission co-infection tuberculosis in HIV community

NASA Astrophysics Data System (ADS)

Lusiana, V.; Putra, P. S.; Nuraini, N.; Soewono, E.

2017-03-01

TB and HIV infection have the effect of deeply on assault the immune system, since they can afford to weaken host immune respone through a mechanism that has not been fully understood. HIV co-infection is the stongest risk factor for progression of M. tuberculosis to active TB disease in HIV individuals, as well as TB has been accelerated to progression HIV infection. In this paper we create a model of transmission co-infection TB in HIV community, dynamic system with ten compartments built in here. Dynamic analysis in this paper mentioned ranging from disease free equilibrium conditions, endemic equilibrium conditions, basic reproduction ratio, stability analysis and numerical simulation. Basic reproductive ratio were obtained from spectral radius the next generation matrix of the model. Numerical simulations are built to justify the results of the analysis and to see the changes in the dynamics of the population in each compartment. The sensitivity analysis indicates that the parameters affecting the population dynamics of TB in people with HIV infection is parameters rate of progression of individuals from the exposed TB class to the active TB, treatment rate of exposed TB individuals, treatment rate of infectious (active TB) individuals and probability of transmission of TB infection from an infective to a susceptible per contact per unit time. We can conclude that growing number of infections carried by infectious TB in people with HIV infection can lead to increased spread of disease or increase in endemic conditions.

Gallium nanoparticles facilitate phagosome maturation and inhibit growth of virulent Mycobacterium tuberculosis in macrophages.

PubMed

Choi, Seoung-Ryoung; Britigan, Bradley E; Moran, David M; Narayanasamy, Prabagaran

2017-01-01

New treatments and novel drugs are required to counter the growing problem of drug-resistant strains of Mycobacterium tuberculosis (M.tb). Our approach against drug resistant M.tb, as well as other intracellular pathogens, is by targeted drug delivery using nanoformulations of drugs already in use, as well as drugs in development. Among the latter are gallium (III) (Ga)-based compounds. In the current work, six different types of Ga and rifampin nanoparticles were prepared in such a way as to enhance targeting of M.tb infected-macrophages. They were then tested for their ability to inhibit growth of a fully pathogenic strain (H37Rv) or a non-pathogenic strain (H37Ra) of M.tb. Encapsulating Ga in folate- or mannose-conjugated block copolymers provided sustained Ga release for 15 days and significantly inhibited M.tb growth in human monocyte-derived macrophages. Nanoformulations with dendrimers encapsulating Ga or rifampin also showed promising anti-tuberculous activity. The nanoparticles co-localized with M.tb containing phagosomes, as measured by detection of mature cathepsin D (34 kDa, lysosomal hydrogenase). They also promoted maturation of the phagosome, which would be expected to increase macrophage-mediated killing of the organism. Delivery of Ga or rifampin in the form of nanoparticles to macrophages offers a promising approach for the development of new therapeutic anti-tuberculous drugs.

Gallium nanoparticles facilitate phagosome maturation and inhibit growth of virulent Mycobacterium tuberculosis in macrophages

PubMed Central

Choi, Seoung-ryoung; Britigan, Bradley E.; Moran, David M.

2017-01-01

New treatments and novel drugs are required to counter the growing problem of drug-resistant strains of Mycobacterium tuberculosis (M.tb). Our approach against drug resistant M.tb, as well as other intracellular pathogens, is by targeted drug delivery using nanoformulations of drugs already in use, as well as drugs in development. Among the latter are gallium (III) (Ga)-based compounds. In the current work, six different types of Ga and rifampin nanoparticles were prepared in such a way as to enhance targeting of M.tb infected-macrophages. They were then tested for their ability to inhibit growth of a fully pathogenic strain (H37Rv) or a non-pathogenic strain (H37Ra) of M.tb. Encapsulating Ga in folate- or mannose-conjugated block copolymers provided sustained Ga release for 15 days and significantly inhibited M.tb growth in human monocyte-derived macrophages. Nanoformulations with dendrimers encapsulating Ga or rifampin also showed promising anti-tuberculous activity. The nanoparticles co-localized with M.tb containing phagosomes, as measured by detection of mature cathepsin D (34 kDa, lysosomal hydrogenase). They also promoted maturation of the phagosome, which would be expected to increase macrophage-mediated killing of the organism. Delivery of Ga or rifampin in the form of nanoparticles to macrophages offers a promising approach for the development of new therapeutic anti-tuberculous drugs. PMID:28542623

Evaluation of Immigrant Tuberculosis Screening in Industrialized Countries

PubMed Central

Pareek, Manish; Baussano, Iacopo; Abubakar, Ibrahim; Dye, Christopher

2012-01-01

In industrialized countries, tuberculosis (TB) cases are concentrated among immigrants and driven by reactivation of imported latent TB infection (LTBI). We examined mechanisms used to screen immigrants for TB and LTBI by sending an anonymous, 18-point questionnaire to 31 member countries of the Organisation for Economic Co-operation and Development. Twenty-nine (93.5%) of 31 responded; 25 (86.2%) screened immigrants for active TB. Fewer countries (16/29, 55.2%) screened for LTBI. Marked variations were observed in targeted populations for age (range <5 years of age to all age groups) and TB incidence in countries of origin of immigrants (>20 cases/100,000 population to >500 cases/100,000). LTBI screening was conducted in 11/16 countries by using the tuberculin skin test. Six countries used interferon-γ release assays, primarily to confirm positive tuberculin skin test results. Industrialized countries performed LTBI screening infrequently and policies varied widely. There is an urgent need to define the cost-effectiveness of LTBI screening strategies for immigrants. PMID:22931959

Primary gingival tuberculosis in pregnancy: A rare combination.

PubMed

Sharma, Shweta; Ahad, Abdul; Gupta, Narinder Dev; Sharma, Vivek Kumar

2018-01-01

Tuberculosis (TB), a common chronic-specific granulomatous disease, has become rare in the developed countries. However, it is still a common cause of morbidity and mortality in India. Although it commonly involves the lungs, its presentation in the oral cavity is quite uncommon. The very rare incidence of primary gingival TB, particularly in the absence of active pulmonary involvement often leads to misdiagnosis. Clinical features of oral lesions may include ulceration, nodules, granulomas, and fissures. TB in pregnant women is a major cause of obstetric complications and increased risk of maternal and child mortality. This report highlights a rare case of primary TB of gingiva, presenting as severe gingival overgrowth in a patient with 4 th month of pregnancy. This case strongly suggests the importance of suspecting TB as the differential diagnosis of gingival overgrowth and therefore, playing a critical role in the early detection and treatment. Interdisciplinary collaboration for diagnosis and management resulted in the successful outcome and prevented the obstetric complications in this case.

Diagnostic performance of a seven-marker serum protein biosignature for the diagnosis of active TB disease in African primary healthcare clinic attendees with signs and symptoms suggestive of TB.

PubMed

Chegou, Novel N; Sutherland, Jayne S; Malherbe, Stephanus; Crampin, Amelia C; Corstjens, Paul L A M; Geluk, Annemieke; Mayanja-Kizza, Harriet; Loxton, Andre G; van der Spuy, Gian; Stanley, Kim; Kotzé, Leigh A; van der Vyver, Marieta; Rosenkrands, Ida; Kidd, Martin; van Helden, Paul D; Dockrell, Hazel M; Ottenhoff, Tom H M; Kaufmann, Stefan H E; Walzl, Gerhard

2016-09-01

User-friendly, rapid, inexpensive yet accurate TB diagnostic tools are urgently needed at points of care in resource-limited settings. We investigated host biomarkers detected in serum samples obtained from adults with signs and symptoms suggestive of TB at primary healthcare clinics in five African countries (Malawi, Namibia, South Africa, The Gambia and Uganda), for the diagnosis of TB disease. We prospectively enrolled individuals presenting with symptoms warranting investigation for pulmonary TB, prior to assessment for TB disease. We evaluated 22 host protein biomarkers in stored serum samples using a multiplex cytokine platform. Using a pre-established diagnostic algorithm comprising of laboratory, clinical and radiological findings, participants were classified as either definite TB, probable TB, questionable TB status or non-pulmonary TB. Of the 716 participants enrolled, 185 were definite and 29 were probable TB cases, 6 had questionable TB disease status, whereas 487 had no evidence of TB. A seven-marker biosignature of C reactive protein, transthyretin, IFN-γ, complement factor H, apolipoprotein-A1, inducible protein 10 and serum amyloid A identified on a training sample set (n=491), diagnosed TB disease in the test set (n=210) with sensitivity of 93.8% (95% CI 84.0% to 98.0%), specificity of 73.3% (95% CI 65.2% to 80.1%), and positive and negative predictive values of 60.6% (95% CI 50.3% to 70.1%) and 96.4% (95% CI 90.5% to 98.8%), respectively, regardless of HIV infection status or study site. We have identified a seven-marker host serum protein biosignature for the diagnosis of TB disease irrespective of HIV infection status or ethnicity in Africa. These results hold promise for the development of a field-friendly point-of-care screening test for pulmonary TB. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Matrix metalloproteinases and tissue damage in HIV-tuberculosis immune reconstitution inflammatory syndrome

PubMed Central

Tadokera, Rebecca; Meintjes, Graeme A; Wilkinson, Katalin A; Skolimowska, Keira H; Walker, Naomi; Friedland, Jon S; Maartens, Gary; Elkington, Paul T G; Wilkinson, Robert J

2014-01-01

The HIV-TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) can complicate combined treatments for HIV-1 and TB. Little is known about tissue damage in TB-IRIS. Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix and consequently may play a role in such immunopathology. Here we investigated the involvement of MMPs in TB-IRIS. We determined MMP transcript abundance and secreted protein in Mycobacterium tuberculosis stimulated PBMCs from 22 TB-IRIS patients and 22 non-IRIS controls. We also measured MMP protein levels in corresponding serum and the effect of prednisone — which reduces the duration of symptoms in IRIS patients — or placebo treatment on MMP transcript and circulating MMP protein levels. PBMCs from TB-IRIS had increased MMP-1,-3,-7, and-10 transcript levels when compared with those of controls at either 6 or 24 h. Similarly, MMP-1,-3,-7, and-10 protein secretion in stimulated cultures was higher in TB-IRIS than in controls. Serum MMP-7 concentration was elevated in TB-IRIS and 2 weeks of corticosteroid therapy decreased this level, although not significantly. TB-IRIS is associated with a distinct pattern of MMP gene and protein activation. Modulation of dysregulated MMP activity may represent a novel therapeutic approach to alleviate TB-IRIS in HIV-TB patients undergoing treatment. PMID:24136296

Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation

PubMed Central

Kübler, André; Luna, Brian; Larsson, Christer; Ammerman, Nicole C.; Andrade, Bruno B.; Orandle, Marlene; Bock, Kevin W.; Xu, Ziyue; Bagci, Ulas; Molura, Daniel J.; Marshall, John; Burns, Jay; Winglee, Kathryn; Ahidjo, Bintou Ahmadou; Cheung, Laurene S.; Klunk, Mariah; Jain, Sanjay K.; Kumar, Nathella Pavan; Babu, Subash; Sher, Alan; Friedland, Jon S.; Elkington, Paul T. G.; Bishai, William R.

2014-01-01

Active tuberculosis (TB) often presents with advanced pulmonary disease, including irreversible lung damage and cavities. Cavitary pathology contributes to antibiotic failure, transmission, morbidity and mortality. Matrix metalloproteinases (MMPs), in particular MMP-1 are implicated in TB pathogenesis. We explored the mechanisms relating MMP/TIMP imbalance to cavity formation in a modified rabbit model of cavitary TB. Our model results in consistent progression of consolidation to human-like cavities (100% by day 28) with resultant bacillary burdens (>107 CFU/g) far greater than those found in matched granulomatous tissue (105 CFU/g). Using a novel, breath-hold computerized tomography scanning and image analysis protocol. We show that cavities develop rapidly from areas of densely consolidated tissue. Radiological change correlated with a decrease in functional lung tissue as estimated by changes in lung density during controlled pulmonary expansion (R2=0.6356, p<0.0001). We demonstrated that the expression of interstitial collagenase (MMP-1) is specifically greater in cavitary compared to granulomatous lesions (p<0.01), and that TIMP-3 significantly decreases at the cavity surface. Our findings demonstrate that an MMP-1/TIMP imbalance, is associated with the progression of consolidated regions to cavities containing very high bacterial burdens. Our model provided mechanistic insight, correlating with human disease at the pathological, microbiological and molecular levels,. It also provides a strategy to investigate therapeutics in the context of complex TB pathology. We used these findings to predict a MMP/TIMP balance in active TB; and confirmed this in human plasma, revealing the potential of MMP/TIMP levels as key components of a diagnostic matrix aimed at distinguishing active from latent TB (PPV=92.9%; 95%CI 66.1–99.8%, NPV=85.6%; 95%CI 77.0–91.9%). PMID:25186281

Primary lung cancer coexisting with active pulmonary tuberculosis.

PubMed

Varol, Y; Varol, U; Unlu, M; Kayaalp, I; Ayranci, A; Dereli, M S; Guclu, S Z

2014-09-01

Lung cancer and pulmonary tuberculosis (TB) comorbidity is a clinical problem that presents a challenge for the diagnosis and treatment of both diseases. To clarify the clinical and survival characteristics of cases with both lung cancer and active pulmonary TB. From 2008 to 2013, 3350 TB patients admitted to the TB Department of the Chest Diseases Hospital of Izmir, Turkey, were evaluated. In 38 (1.1%) male patients, lung cancer and TB were found to coexist. Almost all of the patients were diagnosed at Stage III (n = 14, 36.8%) or IV (n = 17, 44.7%) lung cancer, whereas four (10.6%) had Stage II and three (7.9%) had Stage I disease. Squamous cell lung cancer was the predominant histology (n = 23, 60.7%). The median overall survival among patients was 13.4 months (95%CI 8.09-18.8). One-year survival rates for patients with Stages I, II, III and IV were respectively 100%, 75%, 57% and 40%. The present study demonstrates that lung cancer combined with active pulmonary TB most frequently presents as squamous cell carcinoma, with a male predominance. The overall survival of lung cancer patients did not change even with concomitant active TB.

Tuberculosis prevalence in an urban jail: 1994 and 1998.

PubMed

White, M C; Tulsky, J P; Portillo, C J; Menendez, E; Cruz, E; Goldenson, J

2001-05-01

Despite a continuing decline in tuberculosis (TB) in the US, jails remain a high-risk setting for the identification of active and latent TB infection (LTBI). The purpose of this study was to document the change in TB prevalence in the San Francisco City and County Jail. Two period prevalence analyses were done, for 1994 and 1998. The sample included all persons booked into jail during the two years. The rates of inmates screened and the prevalence of active TB and LTBI by sex and ethnicity were compared using computerized records. Prevalence of active TB was 72.1 per 100000 jail population for 1998, and did not change significantly from 1994. In 1998 one third of active TB cases were found through jail screening. Latinos represented respectively 20.1% and 17.7% of those booked in 1994 and 1998, but 43.0% and 41.7% of inmates with LTBI. In 1998, being Latino (odds ratio 2.9) and male (odds ratio 1.6) were most strongly associated with LTBI. Screening for TB among jail inmates is an increasingly valuable clinical and epidemiological tool for case-finding and for identifying persons who would benefit from preventive therapy.

Tuberculosis in children with sickle cell anaemia: a retrospective study in French tertiary care centres.

PubMed

Droz, Nina; De Lauzanne, Agathe; Holvoet, Laurent; Missud, Florence; Benkerrou, Malika; Brousse, Valentine; Odièvre, Marie-Hélène; Faye, Albert; Koehl, Berengere

2017-06-01

Tuberculosis (TB) and sickle cell anaemia (SCA) may affect the same population of patients, particularly in Africa but also in high-TB incidence areas in developed countries. However, few data are available from children with SCA who develop TB. The aim of this study was to describe the clinical features and outcome of TB diagnosed in children with SCA. We conducted a retrospective, descriptive study in three referral centre of Sickle Cell Disease in Paris, France. We included 11 patients with SCA who develop TB. The median age at TB diagnosis was 11 years [7.5-14.5]. Two patients were asymptomatic and nine patients were symptomatic. Six patients had pulmonary TB (pulmonary, pleural and mediastinal lesions). Five patients had extrapulmonary TB (osteoarticular TB, hepatic TB, cervical and mediastinal TB). Mycobacterium tuberculosis was isolated in four of the 11 cases. All patients recovered after a median of 6 months of anti-TB treatment. The localisation of TB and outcome after treatment in our SCA patients were similar to the one observed in an age-and sex-matched control group of non-SCA patient with TB. despite the low number of patients included in our study, SCA does not seem to be a risk factor for severe TB. What is Known: • Tuberculosis (TB) remains a global health problem particularly in developing countries, and Sickle cell anaemia (SCA) is currently one of the most common genetic diseases in the world that mainly affects African populations. • Very few data are available on TB in SCA patients. What is New: • The features of TB in children with SCA seem to be comparable to those expected in general population, with favourable outcomes in response to standard treatment. • Monitoring the dosage of anti-TB treatments could be of interest because of the possible impact of SCA on drug metabolism.

Screening of patients with diabetes mellitus for tuberculosis in community health settings in China.

PubMed

Lin, Yan; Innes, Anh; Xu, Lin; Li, Ling; Chen, Jinou; Hou, Jinglong; Mi, Fengling; Kang, Wanli; Harries, Anthony D

2015-08-01

To assess the feasibility and results of screening of patients with DM for TB in routine community health services in China. Agreement on how to screen patients with DM for TB and monitor and record the results was obtained at a stakeholders meeting. Subsequent training was carried out for staff at 10 community health centres, with activities implemented from June 2013 to April 2014. Patients with DM were screened for TB at each clinical visit using a symptom-based enquiry, and those positive to any symptom were referred to the TB clinic for TB investigation. A total of 2942 patients with DM visited these ten clinics. All patients received at least one screening for TB. Two patients were identified as already known to have TB. In total, 278 (9.5% of those screened) who had positive TB symptoms were referred for TB investigations and 209 arrived at the TB centre or underwent a chest radiograph for TB investigation. One patient (0.5% of those investigated) was newly diagnosed with active TB and was started on anti-TB treatment. The TB case notification rate of those screened was 102/100,000. This pilot project shows it is feasible to carry out TB screening among patients with DM in community settings, but further work is needed to better characterise patients with DM at higher risk of TB. This may require a more targeted approach focused on high-risk groups such as those with untreated DM or poorly controlled hyperglycaemia. © 2015 John Wiley & Sons Ltd.

Effect of vibration frequency on agonist and antagonist arm muscle activity.

PubMed

Rodríguez Jiménez, Sergio; Benítez, Adolfo; García González, Miguel A; Moras Feliu, Gerard; Maffiuletti, Nicola A

2015-06-01

This study aimed to assess the effect of vibration frequency (f out) on the electromyographic (EMG) activity of the biceps brachii (BB) and triceps brachii (TB) muscles when acting as agonist and antagonist during static exercises with different loads. Fourteen healthy men were asked to hold a vibratory bar as steadily as possible for 10 s during lying row (pulling) and bench press (pushing) exercise at f out of 0 (non-vibration condition), 18, 31 and 42 Hz with loads of 20, 50, and 80 % of the maximum sustainable load (MSL). The root mean square of the EMG activity (EMGRMS) of the BB and TB muscles was expressed as a function of the maximal EMGRMS for respective muscles to characterize agonist activation and antagonist coactivation. We found that (1) agonist activation was greater during vibration (42 Hz) compared to non-vibration exercise for the TB but not for the BB muscle (p < 0.05); (2) antagonist activation was greater during vibration compared to non-vibration exercise for both BB (p < 0.01) and TB (p < 0.05) muscles; (3) the vibration-induced increase in antagonist coactivation was proportional to vibration f out in the range 18-42 Hz and (4) the vibration-induced increase in TB agonist activation and antagonist coactivation occurred at all loading conditions in the range 20-80 % MSL. The use of high vibration frequencies within the range of 18-42 Hz can maximize TB agonist activation and antagonist activation of both BB and TB muscles during upper limb vibration exercise.

Veterinary drug, 17β-trenbolone promotes the proliferation of human prostate cancer cell line through the Akt/AR signaling pathway.

PubMed

Lee, Hee-Seok; Jung, Da-Woon; Han, Songyi; Kang, Hui-Seung; Suh, Jin-Hyang; Oh, Hyun-Suk; Hwang, Myung-Sil; Moon, Guiim; Park, Yooheon; Hong, Jin-Hwan; Koo, Yong Eui

2018-05-01

Trenbolone acetate (TBA) is a synthetic anabolic steroidal growth factor that is used for rapid muscle development in cattle. The absorbed TBA is hydrolyzed to the active form, 17β-trenbolone (17 TB; 17β-hydroxy-estra-4,9,11-trien-3-one) in meat and milk products, which can cause adverse health effects in humans. Similar to 5α-dihydrotestosterone (DHT), 17 TB was reported to exhibit endocrine disrupting effects on animals and humans due to its androgenic effect via binding to the androgen receptor. The purpose of this study is to investigate the molecular mechanism of cell proliferation in prostate cancer (PCa) cells treated with 17 TB. We found that 17 TB induces AR-dependent cell proliferation in the human prostate cancer cell line, 22Rv1 in a concentration dependent manner. Treatment with 17 TB increased the expression of cell cycle regulatory proteins, cyclin D2/CDK-4 and cyclin E/CDK-2, whereas the expression of p27 was down-regulated. Furthermore, phosphorylation of Rb and activation of E2F were also induced, which suggests the activation of cyclin D2/CDK-4 and cyclin E/CDK-2 in the cells. When 22Rv1 cells were exposed to 30 pM of 17 TB, which is the effective concentration (EC 50 ) value required to observe proliferative effects on 22Rv1 cells, the expression levels of the phosphorylated forms of Akt and GSK3β were increased. This study demonstrates that 17 TB induces AR-dependent proliferation through the modulation of cell cycle-related proteins in the Akt signaling pathway. The present study provides an effective methodology for identifying cell proliferation signaling of veterinary drugs that exert AR agonistic effects. Copyright © 2018 Elsevier Ltd. All rights reserved.

Profiling the human immune response to Mycobacterium tuberculosis by human cytokine array.

PubMed

Chen, Tao; Li, Zhenyan; Yu, Li; Li, Haicheng; Lin, Jinfei; Guo, Huixin; Wang, Wei; Chen, Liang; Zhang, Xianen; Wang, Yunxia; Chen, Yuhui; Liao, Qinghua; Tan, Yaoju; Shu, Yang; Huang, Wenyan; Cai, Changhui; Zhou, Zhongjing; Yu, Meiling; Li, Guozhou; Zhou, Lin; Zhong, Qiu; Bi, Lijun; Zhao, Meigui; Guo, Lina; Zhou, Jie

2016-03-01

Tuberculosis (TB) continues to be one of the most serious infectious diseases in the world, however, no effective biomarkers can be used for rapid screening of latent tuberculosis infection (LTBI) and active TB. In this study, serum cytokines were screened and tested as potential biomarker for TB diagnosis. Cytokine array was used to track the cytokine profile and its dynamic change after TB infection. The different expressions of cytokines were confirmed by ELISA assay. ROC curve analyses were used to evaluate the efficacy of a cytokine or cytokine combination for diagnosis. Eotaxin-2, ICAM-1, MCSF, IL-12p70, and IL-11 were significantly higher in the LTBI individuals. I-309, MIG, Eotaxin-2, IL-8, ICAM-1, IL-6sR, and Eotaxin were significantly higher in active TB patients. ROC curve analyses gave AUCs of 0.843, 0.898, and 0.888 for I-309, MIG, and IL-8, respectively, and 0.894 for the combination panel in active TB diagnosis. IFN-γ/IL-4 and IL-2/TNF-α ratios exhibit dynamic changes in the healthy control and LTBI to different stages of active TB. Serum cytokines, including I-309 and MIG, IL-8, Extoxin-2, ICAM-1 and combinations of cytokines, including IFN-γ/IL-4 and IL-2/TNF-α, can be used as serum biomarkers for LTBI and active TB screening, thus indicating prospective clinical applications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Yield of active screening for tuberculosis among asylum seekers in Germany: a systematic review and meta-analysis

PubMed Central

Bozorgmehr, Kayvan; Razum, Oliver; Saure, Daniel; Joggerst, Brigitte; Szecsenyi, Joachim; Stock, Christian

2017-01-01

All asylum seekers in Germany undergo upon-entry screening for tuberculosis TB, but comprehensive evidence on the yield is lacking. We compared the national estimates with the international literature in a systematic review and meta-analysis of studies reporting the yield of TB, defined as the fraction of active TB cases detected among asylum seekers screened in Germany upon entry. We searched 11 national and international databases for empirical studies and the internet for grey literature published in English or German without restrictions on publication time. Among 1,253 screened articles, we identified six articles reporting the yield of active TB based on German data, ranging from 0.72 (95% confidence interval (CI): 0.45–1.10) to 6.41 (95% CI: 4.19–9.37) per 1,000 asylum seekers. The pooled estimate across all studies was 3.47 (95% CI: 1.78–5.73; I2 = 94.9%; p < 0.0001) per 1,000 asylum seekers. This estimate was in line with international evidence (I2 = 0%; p for heterogeneity 0.55). The meta-analysis of available international estimates resulted in a pooled yield of 3.04 (95% CI: 2.24–3.96) per 1,000. This study provides an estimate across several German federal states for the yield of TB screening in asylum seekers. Further research is needed to develop more targeted screening programmes. PMID:28367795

Increased Interleukin-4 production by CD8 and gammadelta T cells in health-care workers is associated with the subsequent development of active tuberculosis.

PubMed

Ordway, Diane J; Costa, Leonor; Martins, Marta; Silveira, Henrique; Amaral, Leonard; Arroz, Maria J; Ventura, Fernando A; Dockrell, Hazel M

2004-08-15

We evaluated immune responses to Mycobacterium tuberculosis in 10 health-care workers (HCWs) and 10 non-HCWs and correlated their immune status with the development of active tuberculosis (TB). Twenty individuals were randomly recruited, tested, and monitored longitudinally for TB presentation. Peripheral blood mononuclear cells (PBMCs) from donors were stimulated with M. tuberculosis and tested for cell proliferation and the production of interferon (IFN)- gamma, interleukin (IL)-5, and IL-4, by use of enzyme-linked immunosorbent or flow-cytometric assays. HCWs had higher levels of cell proliferation (24,258 cpm) and IFN- gamma (6373 pg/mL) to M. tuberculosis than did non-HCWs (cell proliferation, 11,462 cpm; IFN- gamma, 3228 pg/mL). Six of 10 HCWs showed increased median percentages of CD8+IL-4+ (4.7%) and gammadelta +IL-4+ (2.3%) T cells and progressed to active TB. HCWs who remained healthy showed increased median percentages of CD8+IFN- gamma+ (25.0%) and gammadelta +IFN- gamma+ (8.0%) and lower percentages of CD8+IL-4+ (0.05%) and gammadelta +IL-4+ (0.03%) T cells.

'Multiple-test' approach to the laboratory diagnosis of tuberculosis -perception of medical doctors from Ujjain, India.

PubMed

Purohit, Manju Raj; Sharma, Megha; Rosales-Klintz, Senia; Lundborg, Cecilia Stålsby

2015-08-11

Delay in diagnosis is one of the most important factors for the control of tuberculosis (TB) in endemic countries like India. As laboratory diagnosis is the mainstay for identification of active disease, we aim to explore and understand the opinions of medical doctors about the laboratory diagnosis of TB in Ujjain, India. Sixteen qualified specialist medical doctors from Ujjain were purposefully selected for the study. Individual interviews with the doctors (13 men and 3 women), were conducted. As one interview could not be completed, data from 15 interviews were analyzed using manifest and latent content analysis. Based on perception of the doctors, the theme; 'challenges and need for the laboratory diagnosis of TB' emerged from the following subthemes: (i) Relationship between basic element of the TB diseases process such as 'Symptoms prior to diagnoses' and 'Clinical characteristics of TB', which were not specific enough to diagnose TB (ii) The prevailing conditions such as lack of explicit diagnostic tools, lead to the doctors using the 'multiple tests' or 'empiric treatment' approach (iii) The doctors proposed that there is a need for access to a rapid, single and simple diagnostic test, and a need for awareness and knowledge of the practitioners regarding specific TB investigations, and early referral to improve the situation at resource-limited settings. The medical specialists use a 'multiple test' or 'empiric treatment' approach to diagnose TB. According to the participants, there is a low dependence and uptake of the available laboratory TB investigations by medical practitioners. There is an urgent need to have a specific, simple and reliable test, and a protocol, to improve diagnosis of TB and to prevent development of resistant TB.

M. tuberculosis-Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1.

PubMed

Rajaram, Murugesan V S; Arnett, Eusondia; Azad, Abul K; Guirado, Evelyn; Ni, Bin; Gerberick, Abigail D; He, Li-Zhen; Keler, Tibor; Thomas, Lawrence J; Lafuse, William P; Schlesinger, Larry S

2017-10-03

Despite its prominent role as a C-type lectin (CTL) pattern recognition receptor, mannose receptor (MR, CD206)-specific signaling molecules and pathways are unknown. The MR is highly expressed on human macrophages, regulating endocytosis, phagocytosis, and immune responses and mediating Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages, thereby limiting phagosome-lysosome (P-L) fusion. We identified human MR-associated proteins using phosphorylated and non-phosphorylated MR cytoplasmic tail peptides. We found that MR binds FcRγ-chain, which is required for MR plasma membrane localization and M.tb cell association. Additionally, we discovered that MR-mediated M.tb association triggers immediate MR tyrosine residue phosphorylation and Grb2 recruitment, activating the Rac/Pak/Cdc-42 signaling cascade important for M.tb uptake. MR activation subsequently recruits SHP-1 to the M.tb-containing phagosome, where its activity limits PI(3)P generation at the phagosome and M.tb P-L fusion and promotes M.tb growth. In sum, we identify human MR signaling pathways that temporally regulate phagocytosis and P-L fusion during M.tb infection. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Specificity of a whole blood IGRA in German nursing students

PubMed Central

2011-01-01

Background Interferon-gamma release assays (IGRA) are used for tuberculosis (TB) screening in healthcare workers (HCWs). However, data on specificity of IGRA in serial testing of HCWs is sparse. Therefore the specificity and the negative predictive value of the IGRA - QuantiFERON-TB Gold In-Tube (QFT) - in German nursing students was investigated. Methods 194 nursing students at the start of their professional career were tested with the QFT. 14 nursing students were excluded from the specificity analysis, due to exposure to mycobacterium tuberculosis. Two of these subjects were QFT- positive. None of them developed disease during the year of follow-up. A study group of 180 students, all with very low risk of prior TB infection, remained in the specificity analysis. Subjects were monitored for at least two years with respect to the development of active TB disease. IGRA was performed at the start of the training and after one year. Results The mean age of the study group (n = 180) was 23 years (range 18-53) with 70.9% female and 99.4% German born. The specificity of QFT was 98.9% (178/180; 95% CI 0.96-0.99); lowering the cut-off from 0.35 IU/ml to 0.1 IU/ml would have decreased specificity only slightly to 97.8% (176/180; 95% CI 0.94-0.99). Of the 154 nursing students available for re-testing, one student who initially scored positive reverted to negative, and one student initially negative converted to positive. None of the monitored group with initially negative QFT results developed TB disease, indicating a high negative predictive value of the IGRA in this population. Conclusions Following our data, QFT can serve as an effective tool in pre-employment TB screenings for HCWs. As its negative results were stable over time, specificity of the QFT in serial testing of HCWs is high. As the risk of acquiring TB infection in the German healthcare system appears to be low, our data supports the recommendation of performing TB screening only in those HCWs with known contact to TB patients or infectious materials. PMID:21929799

Addressing knowledge gaps and prevention for tuberculosis-infected Indian adults: a vital part of elimination.

PubMed

DeLuca, Andrea; Dhumal, Gauri; Paradkar, Mandar; Suryavanshi, Nishi; Mave, Vidya; Kohli, Rewa; Shivakumar, Shri Vijay Bala Yogendra; Hulyolkar, Vidula; Gaikwad, Archana; Nangude, Ashwini; Pardeshi, Geeta; Kadam, Dileep; Gupta, Amita

2018-05-02

India plans to eliminate tuberculosis (TB) by 2025, and has identified screening and prevention as key activities. Household contacts (HHCs) of index TB cases are a high-risk population that would benefit from rapid implementation of these strategies. However, best practices for TB prevention and knowledge gaps among HHCs have not been studied. We evaluated TB knowledge and understanding of prevention among tuberculin skin-test (TST) positive HHCs. While extensive information is available in other high-burden settings regarding TB knowledge gaps, identifying how Indian adult contacts view their transmission risk and prevention options may inform novel screening algorithms and education efforts that will be part of the new elimination plan. We approached adult HHC to administer a questionnaire on TB knowledge and understanding of infection. Over 1 year, 100 HHC were enrolled at a tertiary hospital in Pune, India. The study population was 61% (n = 61) female, with a mean age of 36.6 years (range 18-67, SD = 12). Education levels were high, with 78 (78%) having at least a high school education, and 23 (24%) had at least some college education. Four (4%) of our participants were HIV-infected. General TB knowledge among HHC was low, with a majority of participants believing that you can get TB from sharing dishes (70%) or touching something that has been coughed on (52%). Understanding of infection was also low, with 42% believing that being skin-test positive means you have disease. To assess readiness for preventive therapy, we asked participants whether they are at a higher risk of progressing to active disease because of their LTBI status. Fifty-four (55%) felt that they are at higher risk. Only 8% had heard of preventive therapy. Our TB knowledge survey among HHCs with evidence of recent exposure found that knowledge is poor and families are confused about transmission in the household. It is imperative that the Indian program develop tools and incentives that can be used to educate TB cases and their families on what infected HHCs can do to prevent disease, including preventive therapy.

C-reactive protein as a screening test for HIV-associated pulmonary tuberculosis prior to antiretroviral therapy in South Africa.

PubMed

Shapiro, Adrienne E; Hong, Ting; Govere, Sabina; Thulare, Hilary; Moosa, Mahomed-Yunus; Dorasamy, Afton; Wallis, Carole L; Celum, Connie L; Grosset, Jacques; Drain, Paul K

2018-05-28

There is an urgent need for more accurate screening tests for tuberculosis(TB). We assessed the diagnostic accuracy of C-reactive protein (CRP) as a screening test for active TB in HIV-infected ambulatory adults. CRP levels were measured in blood collected at the time of HIV testing.Diagnostic accuracy of CRP for pulmonary TB was calculated (reference standard: TB culture), compared to the WHO 4-symptom screen, consisting of cough, fever, night sweats, and weight loss. Diagnostic accuracy was also calculated for CRP in a larger cohort of HIV-infected adults with a positive symptom screen (reference standard: clinical or microbiological TB). Among 425 HIV-infected outpatients systematically tested for pulmonary TB, TB culture was positive in 42 (10%), 279 (66%) had at least one TB-related symptom and 197 (46%) had a CRP >5 mg/L. The sensitivity of CRP and the TB symptom screen to detect TB was the same (90.5%; 95%CI 77.4-97.3) but specificity of CRP was higher than for the TB symptom screen (58.5% vs. 37.1%, p<0.001). Of persons with no symptoms and normal CRP, 99 (98%) had no TB. In another cohort of 749 patients presenting with at least one TB-related symptom and clinically evaluated, CRP had a sensitivity of 98.7% and specificity of 48.3%. In HIV-infected outpatients, CRP was as sensitive but substantially more specific than TB symptom screening. Use of CRP as a screening tool to exclude active TB could identify the same number of HIV-associated TB cases, but reduce the use of diagnostic sputum testing in TB-endemic regions.

Design, syntheses, and anti-tuberculosis activities of conjugates of piperazino-1,3-benzothiazin-4-ones (pBTZs) with 2,7-dimethylimidazo [1,2-a]pyridine-3-carboxylic acids and 7-phenylacetyl cephalosporins.

PubMed

Majewski, Mark W; Tiwari, Rohit; Miller, Patricia A; Cho, Sanghyun; Franzblau, Scott G; Miller, Marvin J

2016-04-15

Tuberculosis (TB) remains one of the most threatening diseases in the world and the need for development of new therapies is dire. Herein we describe the rationale for the design and subsequent syntheses and studies of conjugates between pBTZ and both the imidazopyridine and cephalosporin scaffolds. Overall some compounds exhibited notable anti-TB activity in the range of 2-0.2 μM in the Microplate Alamar Blue (MABA) Assay. Copyright © 2016 Elsevier Ltd. All rights reserved.

Undiagnosed pulmonary tuberculosis among prisoners in Malaysia: an overlooked risk for tuberculosis in the community.

PubMed

Al-Darraji, Haider Abdulrazzaq Abed; Altice, Frederick L; Kamarulzaman, Adeeba

2016-08-01

To investigate the prevalence of previously undiagnosed active tuberculosis (TB) cases among prisoners in Malaysia's largest prison using an intensified TB case-finding strategy. From October 2012 to May 2013, prisoners housed in two distinct units (HIV-negative and HIV-positive) were approached to participate in the TB screening study. Consenting prisoners submitted two sputum samples that were examined using GeneXpert MTB/RIF, smear microscopy and liquid culture. Socio-demographic and clinical information was collected and correlates of active TB, defined as having either a positive GeneXpert MTB/RIF or culture results, were assessed using regression analyses. Among the total of 559 prisoners, 442 (79.1%) had complete data; 28.7% were HIV-infected, 80.8% were men and the average age was 36.4 (SD 9.8) years. Overall, 34 (7.7%) had previously undiagnosed active TB, of whom 64.7% were unable to complete their TB treatment in prison due to insufficient time (<6 months) remaining in prison. Previously undiagnosed active TB was independently associated with older age groups (AOR 11.44 and 6.06 for age ≥ 50 and age 40-49 years, respectively) and with higher levels of immunosuppression (CD4 < 200 cells/ml) in HIV-infected prisoners (AOR 3.07, 95% CI 1.03-9.17). The high prevalence of previously undiagnosed active TB in this prison highlights the inadequate performance of internationally recommended case-finding strategies and suggests that passive case-finding policies should be abandoned, especially in prison settings where HIV infection is prevalent. Moreover, partnerships between criminal justice and public health treatment systems are crucial to continue TB treatment after release. © 2016 John Wiley & Sons Ltd.

Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity.

PubMed

Abate, Ebba; Belayneh, Meseret; Idh, Jonna; Diro, Ermias; Elias, Daniel; Britton, Sven; Aseffa, Abraham; Stendahl, Olle; Schön, Thomas

2015-08-01

The impact of intestinal helminth infection on the clinical presentation and immune response during active tuberculosis (TB) infection is not well characterized. Our aim was to investigate whether asymptomatic intestinal helminth infection alters the clinical signs and symptoms as well as the cell mediated immune responses in patients with active TB. Consecutive, newly diagnosed TB patients and healthy community controls (CCs) were recruited in North-west Ethiopia. TB-score, body mass index and stool samples were analyzed. Cells from HIV-negative TB patients (HIV-/TB) and from CCs were analyzed for regulatory T-cells (Tregs) and cytokine responses using flow cytometry and ELISPOT, respectively. A significantly higher ratio of helminth co-infection was observed in TB patients without HIV (Helm+/HIV-/TB) compared to HIV negative CCs, (40% (121/306) versus 28% (85/306), p = 0.003). Helm+/HIV-/TB patients showed significantly increased IL-5 secreting cells compared to Helm-/HIV-/TB (37 SFU (IQR:13-103) versus 2 SFU (1-50); p = 0.02, n = 30). Likewise, levels of absolute Tregs (9.4 (3.2-16.7) cells/μl versus 2.4 (1.1-4.0) cells/μl; p = 0.041) and IL-10 secreting cells (65 SFU (7-196) versus 1 SFU (0-31); p = 0.014) were significantly higher in Helm+/HIV-/TB patients compared to Helm-/HIV-/TB patients. In a multivariate analysis, a lower rate of sputum smear positivity for acid fast bacilli, lower body temperature, and eosinophilia were independently associated with helminth infection in TB patients. Asymptomatic helminth infection is associated with increased regulatory T-cell and Th2-type responses and a lower rate of sputum smear positivity. Further studies are warranted to investigate the clinical and immunological impact of helminth infection in TB patients.

Benefits and challenges of molecular diagnostics for childhood tuberculosis.

PubMed

Gutierrez, Cristina

2016-12-01

Expanding tuberculosis (TB)-diagnostic services, including access to rapid tests, is a World Health Organization (WHO) strategy to accelerate progress toward ending TB. Faster and more sensitive molecular tests capable of diagnosing TB and drug-resistant TB have the technical capacity to address limitations associated with smears and cultures by increasing accuracy and shortening turnaround times as compared with those of these conventional laboratory methods. Nucleic acid amplification assays used to detect and analyze Mycobacterium tuberculosis (MTB)-complex nucleic acids can be used directly on specimens from patients suspected of having TB. Recently, several commercial molecular tests were developed to detect MTB and determine the drug resistance (DR) based on detection of specific genetic mutations conferring resistance. The first to be endorsed by the WHO was molecular line-probe assay technology. This test uses polymerase chain reaction (PCR) and reverse-hybridization methods to rapidly identify MTB and DR-related mutations simultaneously. More recently, the WHO endorsed Xpert MTB/RIF, Cepheid Inc, CA, USA, a fully automated assay used for TB diagnosis that relies upon PCR techniques for detection of TB and rifampicin resistance-related mutations. Other promising molecular TB assays for simplifying PCR-based testing protocols and increasing their accuracy are under development and evaluation. Although we lack a practical gold standard for the diagnosis of childhood TB, its bacteriological confirmation is always recommended to be sought whenever possible prior to a diagnostic decision being made. Conventional diagnostic laboratory TB tests are less efficient for children as compared with adults, because sufficient sputum samples are more difficult to collect from infants and young children, and their disease is often paucibacillary, resulting in smear-negative disease. These inherent challenges associated with childhood TB are due to immunological- and pathophysiological-response differences relative to those observed in adults. Several recent meta-analyses showed low sensitivity estimates of PCR-based TB assays for paucibacillary forms of TB (extrapulmonary TB and smear-negative pulmonary disease), which represent the vast majority of childhood TB cases. Despite the lack of evidence regarding use of the rapid molecular assays to identify TB and detect DR in children, and due to the clinical nature of childhood TB, TB-expert groups recommend including rapid methods for TB identification and DR detection in diagnostic algorithms for children suspected of both smear-positive and -negative pulmonary or extrapulmonary TB, both with or without human immunodeficiency virus (HIV)-coinfection, when combined with standard methods (including clinical, microbiological, and radiological assessment) for diagnosing active TB and conventional DR. Since 2011, the WHO has specifically recommended use of the Xpert MTB/RIF test as an initial diagnostic tool for children with suspected HIV-associated TB or multidrug-resistant TB based on successful treatment data related to adults. Implementation of the rapid molecular assays for rapid detection of TB and DR should occur in laboratories with proven capability to run molecular tests and where quality control systems are implemented. Molecular approaches should be more largely tested in children, given their status as the group in whom the diagnostic dilemma is most pronounced. These tests should also be included in specific childhood TB diagnostic algorithms adapted to the local/national context in combination with other strategies for improving diagnostics, including more effective specimen collection. Copyright © 2016.

Screening for latent and active tuberculosis infection in the elderly at admission to residential care homes: A cost-effectiveness analysis in an intermediate disease burden area.

PubMed

Li, Jun; Yip, Benjamin H K; Leung, Chichiu; Chung, Wankyo; Kwok, Kin On; Chan, Emily Y Y; Yeoh, Engkiong; Chung, Puihong

2018-01-01

Tuberculosis (TB) in the elderly remains a challenge in intermediate disease burden areas like Hong Kong. Given a higher TB burden in the elderly and limited impact of current case-finding strategy by patient-initiated pathway, proactive screening approaches for the high-risk group could be optimal and increasingly need targeted economic evaluations. In this study, we examined whether and under what circumstance the screening strategies are cost-effective compared with no screening strategy for the elderly at admission to residential care homes. A decision analytic process based on Markov model was adopted to evaluate the cost-effectiveness of four strategies: (i) no screening, (ii) TB screening (CXR) and (iii) TB screening (Xpert) represent screening for TB in symptomatic elderly by chest X-ray and Xpert® MTB/RIF respectively, and (iv) LTBI/TB screening represents screening for latent and active TB infection by QuantiFERON®-TB Gold In-Tube and chest X-ray. The target population was a hypothetical cohort of 65-year-old people, using a health service provider perspective and a time horizon of 20 years. The outcomes were direct medical costs, life-years and quality-adjusted life-years (QALYs) measured by incremental cost-effectiveness ratio (ICER). In the base-case analysis, no screening was the most cost-saving; TB screening (CXR) was dominated by TB screening (Xpert); LTBI/TB screening resulted in more life-years and QALYs accrued. The ICERs of LTBI/TB screening were US$19,712 and US$29,951 per QALY gained compared with no screening and TB screening (Xpert), respectively. At the willingness-to-pay threshold of US$50,000 per QALY gained, LTBI/TB screening was the most cost-effective when the probability of annual LTBI reactivation was greater than 0.155% and acceptability of LTBI/TB screening was greater than 38%. In 1,000 iterations of Monte Carlo simulation, the probabilities of no screening, TB screening (CXR), TB screening (Xpert), and LTBI/TB screening to be cost-effective were 0, 1.3%, 20.1%, and 78.6% respectively. Screening for latent and active TB infection in Hong Kong elderly people at admission to residential care homes appears to be highly effective and cost-effective. The key findings may be the next key factor to bring down TB endemic in the elderly population among intermediate TB burden areas.

Development of the food supplement Nyaditum resae as a new tool to reduce the risk of tuberculosis development

PubMed Central

Tukvadze, Nestani; Cardona, Paula; Vashakidze, Sergo; Shubladze, Natalia; Avaliani, Zaza; Vilaplana, Cris; Cardona, Pere-Joan

2017-01-01

Nyaditum resae (NR) is a galenic preparation of heat-killed Mycobacterium manresensis (hkMn). This is a new species that belongs to the Mycobacterium fortuitum complex, and it is present in drinking water—thus, regulatorily speaking, it is considered a food supplement. Preclinical studies in the murine model of active tuberculosis (TB) in the C3HeB/FeJ strain have demonstrated that daily administration of NR containing 103–106 hkMn for 14 days was able to stop the progression toward active TB [1]. The mechanism of action was linked to the induction of low dose tolerance and was related to the increase of Tuberculin Purified Protein Derivative (PPD) memory-specific Tregs (CD4+CD25+CD39+ cells) after ex vivo incubation of splenocytes for 7 days. This increase of Tregs was related to the increase of inter-leukin (IL)-10 in the spleen and in the reduction of IL-17 in the lungs, where there was also a reduction in bacillary load and the pathology caused by a reduction of neutrophiles’ infiltration [2]. Two randomized, double-blind placebo-controlled clinical trials (CTs) have been conducted in humans. The NYADATREG study (Clinicaltrials.gov identifier NCT02076139; 2013–2014) was aimed to evaluate the safety and the immunogenicity of two concentrations of NR (containing 104 hkMn and 105 hkMn) versus placebo (all administered orally everyday for 14 days) in tuberculin-positive and tuberculin-negative volunteers (total n = 51). The results demonstrated an excellent safety record, with no differences between groups in terms of adverse effects. A significant increase in PPD-specific memory regulatory T cells was also detected in both NR groups [3]. The NYADAPETRICS study (Clinicaltrials.gov identifier NCT02581579) is evaluating the safety and immunogenicity of NR 105 hkMn (capsule format, orally) in the pediatric population. Currently, an efficacy study (randomized, double-blinded, placebo-controlled CT) is being conducted in Georgia. This NYADAGEORG trial includes close contacts of active TB cases with positive sputum not tributaries of chemoprophylaxis (<5-year-old children and HIV-positive individuals), which will receive NR (containing 105 hkMn) or placebo (orally, every day for 14 days). A total of 3300 participants will be recruited in four medical centers around Tbilissi. The participants are monitored by telephone for up to 2 years to evaluate the incidence of active TB. The hypothesis is that the NR group will exhibit a 40% reduction in expected TB incidence. Thus, the anticipated TB incidence will be 3% in the NR group versus 5% in the placebo group. The CT is projected to end by 2021 (Clinicaltrials.gov identifier NCT02897180). The administration of the food supplement NR appears to be a new, easy, safe, and reliable method for reducing the risk of developing active TB, and new CTs must be encouraged to discern the particular efficacy power according to different population characteristics. PMID:28043488

Factors influencing quality of life in patients with active tuberculosis.

PubMed

Marra, Carlo A; Marra, Fawziah; Cox, Victoria C; Palepu, Anita; Fitzgerald, J Mark

2004-10-20

With effective treatment strategies, the focus of tuberculosis (TB) management has shifted from the prevention of mortality to the avoidance of morbidity. As such, there should be an increased focus on quality of life (QoL) experienced by individuals being treated for TB. The objective of our study was to identify areas of QoL that are affected by active TB using focus groups and individual interviews. English, Cantonese, and Punjabi-speaking subjects with active TB who were receiving treatment were eligible for recruitment into the study. Gender-based focus group sessions were conducted for the inner city participants but individual interviews were conducted for those who came to the main TB clinic or were hospitalized. Facilitators used open-ended questions and participants were asked to discuss their experiences of being diagnosed with tuberculosis, what impact it had on their lives, issues around adherence to anti-TB medications and information pertaining to their experience with side effects to these medications. All data were audio-recorded, transcribed verbatim, and analyzed using constant comparative analysis. 39 patients with active TB participated. The mean age was 46.2 years (SD 18.4) and 62% were male. Most were Canadian-born being either Caucasian or Aboriginal. Four themes emerged from the focus groups and interviews. The first describes issues related to the diagnosis of tuberculosis and sub-themes were identified as 'symptoms', 'health care provision', and 'emotional impact'. The second theme discusses TB medication factors and the sub-themes identified were 'adverse effects', 'ease of administration', and 'adherence'. The third theme describes social support and functioning issues for the individuals with TB. The fourth theme describes health behavior issues for the individuals with TB and the identified sub-themes were "behavior modification" and "TB knowledge." Despite the ability to cure TB, there remains a significant impact on QOL. Since much attention is spent on preventative or curative mechanisms, the impact of this condition on QoL is often not considered. Attention to the issues experienced by patients being treated for TB may optimize adherence and treatment success.

Prevalence of hepatitis C virus and human immunodeficiency virus in a group of patients newly diagnosed with active tuberculosis in Porto Alegre, Southern Brazil.

PubMed

Costi, Cintia; Grandi, Tarciana; Halon, Maria Laura; Silva, Márcia Susana Nunes; Silva, Cláudia Maria Dornelles da; Gregianini, Tatiana Schäffer; Possuelo, Lia Gonçalves; Jarczewski, Carla Adriane; Niel, Christian; Rossetti, Maria Lucia Rosa

2017-04-01

Porto Alegre is the Brazilian state capital with second highest incidence of tuberculosis (TB) and the highest proportion of people infected with human immunodeficiency virus (HIV) among patients with TB. Hepatitis C virus (HCV) infection increases the risk of anti-TB drug-induced hepatotoxicity, which may result in discontinuation of the therapy. The aim of this study was (i) to estimate prevalence of HCV and HIV in a group of patients newly diagnosed with active TB in a public reference hospital in Porto Alegre and (ii) to compare demographic, behavioural, and clinical characteristics of patients in relation to their HCV infection status. One hundred and thirty-eight patients with TB were tested for anti-HCV antibody, HCV RNA, and anti-HIV1/2 antibody markers. HCV RNA from real-time polymerase chain reaction (PCR)-positive samples was submitted to reverse transcription and PCR amplification. The 5' non-coding region of the HCV genome was sequenced, and genotypes of HCV isolates were determined. Anti-HCV antibody, HCV RNA, and anti-HIV antibodies were detected in 27 [20%; 95% confidence interval (CI), 13-26%], 17 (12%; 95% CI, 7-18%), and 34 (25%; 95% CI, 17-32%) patients, respectively. HCV isolates belonged to genotypes 1 (n = 12) and 3 (n = 4). Some characteristics were significantly more frequent in patients infected with HCV. Among them, non-white individuals, alcoholics, users of illicit drugs, imprisoned individuals, and those with history of previous TB episode were more commonly infected with HCV (p < 0.05). HCV screening, including detection of anti-HCV antibody and HCV RNA, will be important to improving the management of co-infected patients, given their increased risk of developing TB treatment-related hepatotoxicity.

Down-regulation of Notch signaling pathway reverses the Th1/Th2 imbalance in tuberculosis patients.

PubMed

Li, Qifeng; Zhang, Hui; Yu, Liang; Wu, Chao; Luo, Xinhui; Sun, He; Ding, Jianbing

2018-01-01

Th1/Th2 imbalance to Th2 is of significance in the peripheral immune responses in Tuberculosis (TB) development. However, the mechanisms for Th1/Th2 imbalance are still not well determined. Notch signaling pathway is involved in the peripheral T cell activation and effector cell differentiation. However, whether it affects Th1/Th2 imbalance in TB patients is still not known. Here, we used γ-secretase inhibitor (DAPT) to treat the peripheral blood mononuclear cells (PBMCs) from healthy people or individuals with latent or active TB infection in vitro, respectively. Then, the Th1/Th2 ratios were determined by flow cytometry, and cytokines of IFN-γ, IL-4, IL-10 in the culture supernatant were measured by CBA method. The Notch signal pathway associated proteins Hes1, GATA3 and T-bet were quantitated by real-time PCR or immunoblotting. Our results showed that DAPT effectively inhibited the protein level of Hes1. In TB patients, the Th2 ratio increased in the PBMCs, alone with the high expression of GATA3 and IL-4, resulting in the high ratios of Th2/Th1 and GATA3/T-bet in TB patients. However, Th2 cells ratio decreased after blocking the Notch signaling pathway by DAPT and the Th2/Th1 ratio in TB patients were DAPT dose-dependent, accompanied by the decrease of IL-4 and GATA3. But, its influence on Th1 ratio and Th1 related T-bet and IFN-γ levels were not significant. In conclusion, our results suggest that blocking Notch signaling by DAPT could inhibit Th2 responses and restore Th1/Th2 imbalance in TB patients. Copyright © 2017. Published by Elsevier B.V.

A cost-benefit analysis of a proposed overseas refugee latent tuberculosis infection screening and treatment program.

PubMed

Wingate, La'Marcus T; Coleman, Margaret S; de la Motte Hurst, Christopher; Semple, Marie; Zhou, Weigong; Cetron, Martin S; Painter, John A

2015-12-01

This study explored the effect of screening and treatment of refugees for latent tuberculosis infection (LTBI) before entrance to the United States as a strategy for reducing active tuberculosis (TB). The purpose of this study was to estimate the costs and benefits of LTBI screening and treatment in United States bound refugees prior to arrival. Costs were included for foreign and domestic LTBI screening and treatment and the domestic treatment of active TB. A decision tree with multiple Markov nodes was developed to determine the total costs and number of active TB cases that occurred in refugee populations that tested 55, 35, and 20 % tuberculin skin test positive under two models: no overseas LTBI screening and overseas LTBI screening and treatment. For this analysis, refugees that tested 55, 35, and 20 % tuberculin skin test positive were divided into high, moderate, and low LTBI prevalence categories to denote their prevalence of LTBI relative to other refugee populations. For a hypothetical 1-year cohort of 100,000 refugees arriving in the United States from regions with high, moderate, and low LTBI prevalence, implementation of overseas screening would be expected to prevent 440, 220, and 57 active TB cases in the United States during the first 20 years after arrival. The cost savings associated with treatment of these averted cases would offset the cost of LTBI screening and treatment for refugees from countries with high (net cost-saving: $4.9 million) and moderate (net cost-saving: $1.6 million) LTBI prevalence. For low LTBI prevalence populations, LTBI screening and treatment exceed expected future TB treatment cost savings (net cost of $780,000). Implementing LTBI screening and treatment for United States bound refugees from countries with high or moderate LTBI prevalence would potentially save millions of dollars and contribute to United States TB elimination goals. These estimates are conservative since secondary transmission from tuberculosis cases in the United States was not considered in the model.

Tracking and Treating Mobile Populations. The TB Net System. Migrant Clinicians Network Monograph Series. = El Sistema de Red para la TB.

ERIC Educational Resources Information Center

Migrant Clinicians Network, Inc., Austin, TX.

A comprehensive tracking and referral network that helps provide continuity of care for mobile populations with active tuberculosis (TB) or TB infection is considered essential for effective treatment of TB. However, the interstate referral system that exists between state health departments has been highly inefficient for serving migrant…

Endogenous thermoregulatory rhythms of squirrel monkeys in thermoneutrality and cold

NASA Technical Reports Server (NTRS)

Robinson, E. L.; Fuller, C. A.

1999-01-01

Whole body heat production (HP) and heat loss (HL) were examined to determine if the free-running circadian rhythm in body temperature (Tb) results from coordinated changes in HP and HL rhythms in thermoneutrality (27 degrees C) as well as mild cold (17 degrees C). Squirrel monkey metabolism (n = 6) was monitored by both indirect and direct calorimetry, with telemetered measurement of Tb and activity. Feeding was also measured. Rhythms of HP, HL, and conductance were tightly coupled with the circadian Tb rhythm at both ambient temperatures (TA). At 17 degrees C, increased HP compensated for higher HL at all phases of the Tb rhythm, resulting in only minor changes to Tb. Parallel compensatory changes of HP and HL were seen at all rhythm phases at both TA. Similar time courses of Tb, HP, and HL in their respective rhythms and the relative stability of Tb during both active and rest periods suggest action of the circadian timing system on Tb set point.

Digital health for the End TB Strategy: developing priority products and making them work

PubMed Central

Timimi, Hazim; Kurosinski, Pascal; Migliori, Giovanni Battista; Van Gemert, Wayne; Denkinger, Claudia; Isaacs, Chris; Story, Alistair; Garfein, Richard S.; do Valle Bastos, Luis Gustavo; Yassin, Mohammed A.; Rusovich, Valiantsin; Skrahina, Alena; Van Hoi, Le; Broger, Tobias; Abubakar, Ibrahim; Hayward, Andrew; Thomas, Bruce V.; Temesgen, Zelalem; Quraishi, Subhi; von Delft, Dalene; Jaramillo, Ernesto; Weyer, Karin; Raviglione, Mario C.

2016-01-01

In 2014, the World Health Organization (WHO) developed the End TB Strategy in response to a World Health Assembly Resolution requesting Member States to end the worldwide epidemic of tuberculosis (TB) by 2035. For the strategy's objectives to be realised, the next 20 years will need novel solutions to address the challenges posed by TB to health professionals, and to affected people and communities. Information and communication technology presents opportunities for innovative approaches to support TB efforts in patient care, surveillance, programme management and electronic learning. The effective application of digital health products at a large scale and their continued development need the engagement of TB patients and their caregivers, innovators, funders, policy-makers, advocacy groups, and affected communities. In April 2015, WHO established its Global Task Force on Digital Health for TB to advocate and support the development of digital health innovations in global efforts to improve TB care and prevention. We outline the group's approach to stewarding this process in alignment with the three pillars of the End TB Strategy. The supplementary material of this article includes target product profiles, as developed by early 2016, defining nine priority digital health concepts and products that are strategically positioned to enhance TB action at the country level. PMID:27230443

Microarray and network-based identification of functional modules and pathways of active tuberculosis.

PubMed

Bian, Zhong-Rui; Yin, Juan; Sun, Wen; Lin, Dian-Jie

2017-04-01

Diagnose of active tuberculosis (TB) is challenging and treatment response is also difficult to efficiently monitor. The aim of this study was to use an integrated analysis of microarray and network-based method to the samples from publically available datasets to obtain a diagnostic module set and pathways in active TB. Towards this goal, background protein-protein interactions (PPI) network was generated based on global PPI information and gene expression data, following by identification of differential expression network (DEN) from the background PPI network. Then, ego genes were extracted according to the degree features in DEN. Next, module collection was conducted by ego gene expansion based on EgoNet algorithm. After that, differential expression of modules between active TB and controls was evaluated using random permutation test. Finally, biological significance of differential modules was detected by pathways enrichment analysis based on Reactome database, and Fisher's exact test was implemented to extract differential pathways for active TB. Totally, 47 ego genes and 47 candidate modules were identified from the DEN. By setting the cutoff-criteria of gene size >5 and classification accuracy ≥0.9, 7 ego modules (Module 4, Module 7, Module 9, Module 19, Module 25, Module 38 and Module 43) were extracted, and all of them had the statistical significance between active TB and controls. Then, Fisher's exact test was conducted to capture differential pathways for active TB. Interestingly, genes in Module 4, Module 25, Module 38, and Module 43 were enriched in the same pathway, formation of a pool of free 40S subunits. Significant pathway for Module 7 and Module 9 was eukaryotic translation termination, and for Module 19 was nonsense mediated decay enhanced by the exon junction complex (EJC). Accordingly, differential modules and pathways might be potential biomarkers for treating active TB, and provide valuable clues for better understanding of molecular mechanism of active TB. Copyright © 2017 Elsevier Ltd. All rights reserved.

Screening of health-care workers for latent tuberculosis infection in a Tertiary Care Hospital.

PubMed

Janagond, Anand Bimari; Ganesan, Vithiya; Vijay Kumar, G S; Ramesh, Arunagiri; Anand, Prem; Mariappan, M

2017-01-01

Health-care workers (HCWs) are at increased risk of acquiring tuberculosis (TB) than the general population. While national-level data on the burden of TB in general population is available from reliable sources, nationally representative data on latent tuberculosis infection (LTBI) burden in HCWs in the high burden countries is lacking. A prospective study was carried out to assess the risk of TB infection among HCWs who directly engage in medical duties. HCWs were recruited between January 2014 and December 2015. A structured questionnaire was used for risk assessment of TB infection among HCWs, including sociodemographic characteristics (e.g., age, gender, period of professional work, and employed position), knowledge of TB prevention and control, and history of professional work. A single-step tuberculin skin test (TST) using 5 international units (IU; 0.1 ml) of tuberculin (purified protein derivative from Mycobacterium bovis Bacillus Calmette-Guérin [BCG]). TB infection was determined using a TST induration ≥10 mm as a cutoff point for TST positivity. TST-positive participants were further subjected to detailed clinical evaluation and chest radiography to rule out active TB. The associations between TB infection and the sociodemographic characteristics, duration of possible exposure to TB while on medical duties, BCG vaccination, and knowledge about TB were estimated using Chi-square test. A two-sided P < 0.05 indicated statistical significance. A total of 206 eligible HCWs signed the informed consent and completed the questionnaires between January 2014 and December 2015. The age of the participants ranged from 18 to 71 years, with a mean age of 27.13 years. TST induration size (mean 6.37 mm) the TST results suggested that 36.8% (76/206) were infected with TB using a TST induration ≥10 mm as a cut-off point. All 76 TST-positive HCWs showed no evidence of active TB in clinical evaluation and chest radiography. However, during the study, two HCWs developed pulmonary TB (both TST baseline test negative). Statistical analysis suggested that age, duration of employment as a health-care professional, literacy status, and working in medical wards/OP/Intensive Care Unit were significantly associated with TB infection. Many studies propose serial tests of LTBI as effective occupational protection strategies. However, practically, it is not feasible because it has to be done at frequent intervals, but how frequently to be done is not clear. Another concern is even if found to have LTBI, there are no clear consensus guidelines about the treatment in high prevalence settings. The prevalence of LTBI is so high in countries like India that affected HCWs could not be exempted from working in high-risk areas. The depth of knowledge of TB prevention and control among HCWs should be improved by regular infection control training.

Effect of Active Case Finding on Prevalence and Transmission of Pulmonary Tuberculosis in Dhaka Central Jail, Bangladesh

PubMed Central

Banu, Sayera; Rahman, Md. Toufiq; Uddin, Mohammad Khaja Mafij; Khatun, Razia; Khan, Md. Siddiqur Rahman; Rahman, Md. Mojibur; Uddin, Syed Iftekhar; Ahmed, Tahmeed; Heffelfinger, James D.

2015-01-01

Background Understanding tuberculosis (TB) transmission dynamics is essential for establishing effective TB control strategies in settings where the burden and risk of transmission are high. The objectives of this study were to evaluate the effect of active screening on controlling TB transmission and also to characterize Mycobacterium tuberculosis strains for investigating transmission dynamics in a correctional setting. Methods The study was carried out in Dhaka Central Jail (DCJ), from October 2005 to February 2010. An active case finding strategy for pulmonary TB was established both at the entry point to the prison and inside the prison. Three sputum specimens were collected from all pulmonary TB suspects and subjected to smear microscopy, culture, and drug susceptibility testing as well as genotyping which included deletion analysis, spoligotyping and analysis of mycobacterial interspersed repetitive units (MIRU). Results A total of 60,585 inmates were screened during the study period. We found 466 inmates with pulmonary TB of whom 357 (77%) had positive smear microscopy results and 109 (23%) had negative smear microscopy results but had positive results on culture. The number of pulmonary TB cases declined significantly, from 49 cases during the first quarter to 8 cases in the final quarter of the study period (p=0.001). Deletion analysis identified all isolates as M. tuberculosis and further identified 229 (70%) strains as ‘modern’ and 100 (30%) strains as ‘ancestral’. Analysis of MIRU showed that 347 strains (85%) exhibited unique patterns, whereas 61 strains (15%) clustered into 22 groups. The largest cluster comprised eight strains of the Beijing M. tuberculosis type. The rate of recent transmission was estimated to be 9.6%. Conclusions Implementation of active screening for TB was associated with a decline in TB cases in DCJ. Implementation of active screening in prison settings might substantially reduce the national burden of TB in Bangladesh. PMID:25933377

Effect of active case finding on prevalence and transmission of pulmonary tuberculosis in Dhaka Central Jail, Bangladesh.

PubMed

Banu, Sayera; Rahman, Md Toufiq; Uddin, Mohammad Khaja Mafij; Khatun, Razia; Khan, Md Siddiqur Rahman; Rahman, Md Mojibur; Uddin, Syed Iftekhar; Ahmed, Tahmeed; Heffelfinger, James D

2015-01-01

Understanding tuberculosis (TB) transmission dynamics is essential for establishing effective TB control strategies in settings where the burden and risk of transmission are high. The objectives of this study were to evaluate the effect of active screening on controlling TB transmission and also to characterize Mycobacterium tuberculosis strains for investigating transmission dynamics in a correctional setting. The study was carried out in Dhaka Central Jail (DCJ), from October 2005 to February 2010. An active case finding strategy for pulmonary TB was established both at the entry point to the prison and inside the prison. Three sputum specimens were collected from all pulmonary TB suspects and subjected to smear microscopy, culture, and drug susceptibility testing as well as genotyping which included deletion analysis, spoligotyping and analysis of mycobacterial interspersed repetitive units (MIRU). A total of 60,585 inmates were screened during the study period. We found 466 inmates with pulmonary TB of whom 357 (77%) had positive smear microscopy results and 109 (23%) had negative smear microscopy results but had positive results on culture. The number of pulmonary TB cases declined significantly, from 49 cases during the first quarter to 8 cases in the final quarter of the study period (p=0.001). Deletion analysis identified all isolates as M. tuberculosis and further identified 229 (70%) strains as 'modern' and 100 (30%) strains as 'ancestral'. Analysis of MIRU showed that 347 strains (85%) exhibited unique patterns, whereas 61 strains (15%) clustered into 22 groups. The largest cluster comprised eight strains of the Beijing M. tuberculosis type. The rate of recent transmission was estimated to be 9.6%. Implementation of active screening for TB was associated with a decline in TB cases in DCJ. Implementation of active screening in prison settings might substantially reduce the national burden of TB in Bangladesh.

Sensitized terbium(III) macrocyclic-phthalimide complexes as luminescent pH switches.

PubMed

Chen, Gaoyun; Wardle, Nicholas J; Sarris, Jason; Chatterton, Nicholas P; Bligh, S W Annie

2013-10-21

Four new macrocyclic-phthalimide ligands were synthesised via the coupling of N-(3-bromopropyl)phthalimide either to cyclen (1,4,7,10-tetraazacyclododecane) itself or its carboxylate-functionalized analogues, and photophysical studies were carried out on their corresponding Tb(III) complexes in aqueous media as a function of pH. Luminescence intensities of Tb·L1a–Tb·L3a were in ‘switched off’ mode under acidic conditions (pH < 4), and were activated on progression to basic conditions as the phthalimido functions therein were hydrolysed to their corresponding phthalamates Tb·L1b–Tb·L3b. Emission of phthalamate-based macrocyclic Tb(III) complexes Tb·L1b–Tb·L3b was in ‘switched on’ mode between pH 4 and 11, exhibiting high quantum yields (Φ) and long lifetimes (τ) of the order of milliseconds at pH ~ 6. Tb(III) emissions were found to decline with increasing number of chromophores. The values of Φ and τ were 46% and 2.4 ms respectively for Tb·L1b at pH ~ 6 when activated. This is the best pH-dependent sensor based on a Tb(III) complex reported to date, benefiting from the macrocyclic architecture of the ligand.

High prevalence and risk factors associated with latent tuberculous infection in two Colombian prisons.

PubMed

Rueda, Z V; Arroyave, L; Marin, D; López, L; Keynan, Y; Giraldo, M R; Pulido, H; Arbeláez, M P

2014-10-01

Two prisons in Medellín and Itagüí, Colombia. To determine the prevalence of tuberculin skin test (TST) positivity in prisoners and the annual risk of tuberculous infection (ARTI), to identify risk factors associated with a positive result, and to describe progression to active disease. Cross-sectional study. Inmates were included if time of incarceration was ⩾1 year and excluded if subjects had had previous or active tuberculosis (TB), or conditions that could hamper TST administration or interpretation. We screened 1014 inmates. The overall prevalence of TST positivity was 77.6%. The first TST administration resulted in 66% positivity, and the second TST an additional 11.6%. In Prison One, the ARTI was 5.09% in high TB incidence cell blocks and 2.72% in low TB incidence blocks. In Prison Two, the ARTI was 2.77%. Risk factors associated with TST positivity were history of previous incarceration and length of incarceration. Among all those included in the study, four individuals developed active pulmonary TB. Prevalence of TST positivity in prisoners and the ARTI were higher than in the general population, but differed between prisons; it is important to apply a second TST to avoid an overestimation of converters during follow-up.

PEPFAR support for the scaling up of collaborative TB/HIV activities.

PubMed

Howard, Andrea A; Gasana, Michel; Getahun, Haileyesus; Harries, Anthony; Lawn, Stephen D; Miller, Bess; Nelson, Lisa; Sitienei, Joseph; Coggin, William L

2012-08-15

The US President's Emergency Plan for AIDS Relief (PEPFAR) has supported a comprehensive package of care in which interventions to address HIV-related tuberculosis (TB) have received increased funding and support in recent years. PEPFAR's TB/HIV programming is based on the World Health Organization's 12-point policy for collaborative TB/HIV activities, which are integrated into PEPFAR annual guidance. PEPFAR implementing partners have provided crucial support to TB/HIV collaboration, and as a result, PEPFAR-supported countries in sub-Saharan Africa have made significant gains in HIV testing and counseling of TB patients and linkages to HIV care and treatment, intensified TB case finding, and TB infection control. PEPFAR's support of TB/HIV integration has also included significant investment in health systems, including improved laboratory services and educating and enlarging the workforce. The scale-up of antiretroviral therapy along with support of programs to increase HIV counseling and testing and improve linkage and retention in HIV care may have considerable impact on TB morbidity and mortality, if used synergistically with isoniazid preventive therapy, intensified case finding, and infection control. Issues to be addressed by future programming include accelerating implementation of isoniazid preventive therapy, increasing access and ensuring appropriate use of new TB diagnostics, supporting early initiation of antiretroviral therapy for HIV-infected TB patients, and strengthening systems to monitor and evaluate program implementation.

PEPFAR Support for the Scaling Up of Collaborative TB/HIV Activities

PubMed Central

Howard, Andrea A.; Gasana, Michel; Getahun, Haileyesus; Harries, Anthony; Lawn, Stephen D.; Miller, Bess; Nelson, Lisa; Sitienei, Joseph; Coggin, William L.

2014-01-01

The US President’s Emergency Plan for AIDS Relief (PEPFAR) has supported a comprehensive package of care in which interventions to address HIV-related tuberculosis (TB) have received increased funding and support in recent years. PEPFAR’s TB/HIV programming is based on the World Health Organization 12-point policy for collaborative TB/HIV activities, which are integrated into PEPFAR annual guidance. PEPFAR implementing partners have provided crucial support to TB/HIV collaboration, and as a result PEPFAR-supported countries in sub-Saharan Africa have made significant gains in HIV testing and counseling of TB patients and linkages to HIV care and treatment, intensified TB case finding, and TB infection control. PEPFAR’s support of TB/HIV integration has also included significant investment in health systems, including improved laboratory services and educating and enlarging the workforce. The scale-up of antiretroviral therapy along with support of programs to increase HIV counseling and testing and improve linkage and retention in HIV care may have considerable impact on TB morbidity and mortality, if used synergistically with isoniazid preventive therapy (IPT), intensified case finding and infection control. Issues to be addressed by future programming include accelerating implementation of IPT, increasing access and ensuring appropriate use of new TB diagnostics, supporting early initiation of antiretroviral therapy for HIV-infected TB patients, and strengthening systems to monitor and evaluate program implementation. PMID:22797735

Tuberculin-Specific T Cells Are Reduced in Active Pulmonary Tuberculosis Compared to LTBI or Status Post BCG Vaccination

PubMed Central

Streitz, Mathias; Fuhrmann, Stephan; Powell, Fiona; Quassem, Ali; Nomura, Laurel; Maecker, Holden; Martus, Peter; Volk, Hans-Dieter

2011-01-01

Functional characteristics of tuberculosis (TB)–specific CD4 T cells were studied in clinically active pulmonary TB (n = 21) and high TB exposure including LTBI (n = 17). Following tuberculin stimulation, activated CD4 T cells were identified by flow-cytometry (CD154 up-regulation, degranulation, interferon γ [IFN-γ], tumor necrosis factor α [TNF-α], and interleukin 2 [IL-2\\ production). Interestingly, CD154 up-regulation accounted for ∼80% of activated CD4 T cells in the active TB group but just 40% in the controls, whereas IFN-γ accounted for only ∼50% of activated cells in each group. The frequencies of CD4 T cells displaying at least 1 activation marker discriminated better between the groups than those displaying degranulation or IFN-γ production alone. PMID:21186260

ESMPE: A combined strategy for school tuberculosis prevention and control proposed by Dalian, China.

PubMed

Wang, Xichen; Jiang, Hongbo; Wang, Xuemei; Liu, Hongyu; Zhou, Ling; Lu, Xiwei

2017-01-01

Although China has paid more attention on the prevention and control of tuberculosis (TB) in schools, several unsolved questions in this field still threaten the progress of TB control. Therefore, there is an urgent need to develop a systematic and practical strategy for Chinese school TB prevention and control system. In this study, we aimed to assess the feasibility of a combined strategy named ESMPE (examination, screening, monitoring, prevention and education) that adhere to the basic principles of Chinese schools TB control strategy. The ESMPE strategy included five sections, namely TB screening during physical examination for the school freshmen entrances, screening of close contacts, monitoring of high-risk schools, preventive treatment and TB education. The effectiveness of ESMPE strategy was evaluated from 2011 to 2016. The original data were provided by the Dalian Tuberculosis Hospital. Descriptive analysis and nonparametric tests were used for comparing statistical differences of results between different years. The detection rate of active pulmonary TB in school freshmen was decreased from 2011 to 2016 (χ2 = 41.941, P = 6.0551E-8). 97.22% (17,043/17,530) of close contacts experienced close contacts screening, and the secondary attack rate (SAR) of TB in schools fell by 146.35/105 from 2011 to 2012, and finally reduced to 85.57/105 in 2016. There was a significant correlation between SAR of student TB and the rate of screened close contacts (r = -0.924, P = 0.009). TB incidence of five monitored schools had a substantial decline after receiving monitoring, and this declining trend continued in 2016. Due to the TB education and advanced screening methods, the mean of diagnostic delay time in students with TB was shortened (15.71 days), while still fewer latent TB infection students received preventive treatment (30.38%). The ESMPE strategy has shown a favorable effect on TB prevention and control in Dalian schools. More systematic evidence is needed on the effect of this strategy in reducing the incidence of TB in schools from other settings prior to its further scaling-up in China.

Natively Inhibited Trypanosoma brucei Cathepsin B Structure Determined by Using an X-ray Laser

PubMed Central

DePonte, Daniel P.; White, Thomas A.; Rehders, Dirk; Barty, Anton; Stellato, Francesco; Liang, Mengning; Barends, Thomas R.M.; Boutet, Sébastien; Williams, Garth J.; Messerschmidt, Marc; Seibert, M. Marvin; Aquila, Andrew; Arnlund, David; Bajt, Sasa; Barth, Torsten; Bogan, Michael J.; Caleman, Carl; Chao, Tzu-Chiao; Doak, R. Bruce; Fleckenstein, Holger; Frank, Matthias; Fromme, Raimund; Galli, Lorenzo; Grotjohann, Ingo; Hunter, Mark S.; Johansson, Linda C.; Kassemeyer, Stephan; Katona, Gergely; Kirian, Richard A.; Koopmann, Rudolf; Kupitz, Chris; Lomb, Lukas; Martin, Andrew V.; Mogk, Stefan; Neutze, Richard; Shoeman, Robert L.; Steinbrener, Jan; Timneanu, Nicusor; Wang, Dingjie; Weierstall, Uwe; Zatsepin, Nadia A.; Spence, John C. H.; Fromme, Petra; Schlichting, Ilme; Duszenko, Michael; Betzel, Christian; Chapman, Henry N.

2013-01-01

The Trypanosoma brucei cysteine protease cathepsin B (TbCatB), which is involved in host protein degradation, is a promising target to develop new treatments against sleeping sickness, a fatal disease caused by this protozoan parasite. The structure of the mature, active form of TbCatB has so far not provided sufficient information for the design of a safe and specific drug against T. brucei. By combining two recent innovations, in vivo crystallization and serial femtosecond crystallography, we obtained the room-temperature 2.1 angstrom resolution structure of the fully glycosylated precursor complex of TbCatB. The structure reveals the mechanism of native TbCatB inhibition and demonstrates that new biomolecular information can be obtained by the “diffraction-before-destruction” approach of x-ray free-electron lasers from hundreds of thousands of individual microcrystals. PMID:23196907

The current status, challenges, and future developments of new tuberculosis vaccines.

PubMed

Gong, Wenping; Liang, Yan; Wu, Xueqiong

2018-03-30

Mycobacterium tuberculosis complex causes tuberculosis (TB), one of the top 10 causes of death worldwide. TB results in more fatalities than multi-drug resistant (MDR) HIV strain related coinfection. Vaccines play a key role in the prevention and control of infectious diseases. Unfortunately, the only licensed preventive vaccine against TB, bacilli Calmette-Guérin (BCG), is ineffective for prevention of pulmonary TB in adults. Therefore, it is very important to develop novel vaccines for TB prevention and control. This literature review provides an overview of the innate and adaptive immune response during M. tuberculosis infection, and presents current developments and challenges to novel TB vaccines. A comprehensive understanding of vaccines in preclinical and clinical studies provides extensive insight for the development of safer and more efficient vaccines, and may inspire new ideas for TB prevention and treatment.

Assessment of the influence of direct tobacco smoke on infection and active TB management.

PubMed

Altet, Neus; Latorre, Irene; Jiménez-Fuentes, María Ángeles; Maldonado, José; Molina, Israel; González-Díaz, Yoel; Milà, Celia; García-García, Esther; Muriel, Beatriz; Villar-Hernández, Raquel; Laabei, Maisem; Gómez, Andromeda-Celeste; Godoy, Pere; de Souza-Galvão, Maria Luiza; Solano, Segismundo; Jiménez-Ruiz, Carlos A; Domínguez, Jose

2017-01-01

Smoking is a risk factor for tuberculosis (TB) infection and disease progression. Tobacco smoking increases susceptibility to TB in a variety of ways, one of which is due to a reduction of the IFN-γ response. Consequently, an impaired immune response could affect performance of IFN-γ Release Assays (IGRAs). In the present study, we assess the impact of direct tobacco smoking on radiological manifestations, sputum conversion and immune response to Mycobacterium tuberculosis, analyzing IFN-γ secretion by IGRAs. A total of 525 participants were studied: (i) 175 active pulmonary TB patients and (ii) 350 individuals coming from contact tracing studies, 41 of whom were secondary TB cases. Clinical, radiological and microbiological data were collected. T-SPOT.TB and QFN-G-IT were processed according manufacturer's instructions. In smoking patients with active TB, QFN-G-IT (34.4%) and T-SPOT.TB (19.5%) had high frequencies of negative results. In addition, by means of an unconditional logistic regression, smoking was a main factor associated with IGRAs' false-negative results (aOR: 3.35; 95%CI:1.47-7.61; p<0.05). Smoking patients with active TB presented a high probability of having cavitary lesions (aOR: 1.88; 95%CI:1.02-3.46;p<0.05). Mean culture negativization (months) ± standard deviation (SD) was higher in smokers than in non-smokers (2.47±1.3 versus 1.69±1.4). Latent TB infection (LTBI) was favored in smoking contacts, being a risk factor associated with infection (aOR: 11.57; 95%CI:5.97-22.41; p<0.00005). The IFN-γ response was significantly higher in non-smokers than in smokers. Smoking quantity and IFN-γ response analyzed by IGRAs were dose-dependent related. Smoking had a negative effect on radiological manifestations, delaying time of sputum conversion. Our data establish a link between tobacco smoking and TB due to a weakened IFN-γ response caused by direct tobacco smoke.

The risk factor of false-negative and false-positive for T-SPOT.TB in active tuberculosis.

PubMed

Di, Li; Li, Yan

2018-02-01

T-SPOT.TB is a promising diagnosis tool to identify both pulmonary tuberculosis and extrapulmonary tuberculosis, as well as latent tuberculosis; however, the factors that affect the results of T-SPOT.TB remains unclear. In this study, we aim to figure out the risk factor of T-SPOT.TB for active TB. A total of 349 patients were recruited between January 1st, 2016 and January 22st, 2017 at Renmin Hospital of Wuhan University, including 98 subjects with TB and 251 subjects with non-TB disease, and received T-SPOT.TB (Oxford Immunotec Ltd). Statistics were analyzed by SPSS 19.0 using logistic regression. The overall specificity and sensitivity of the T-SPOT.TB was 92.83% (233/251; 95%CI 0.8872-0.9557) and 83.67% (82/98; 95%CI 0.7454-0.9010), respectively. Patients with tuberculous meningitis were more likely to have false-negative results (OR 17.4, 95%CI 3.068-98.671; P<.001) while patients with cured TB tended to induce false-positive results (OR 30.297; 95%CI 7.069-129.849; P<.001). The results were not affected by sex, age, onset time, smoke, alcohol, treatment, allergic history, co-morbidity, TB (exclude tuberculous meningitis) (P>.05). Tuberculous meningitis was a risk factor of false-negative for T-SPOT.TB, while cured TB was a risk factor of false-positive. © 2017 Wiley Periodicals, Inc.

Analysis of Factors Influencing Diagnostic Accuracy of T-SPOT.TB for Active Tuberculosis in Clinical Practice.

PubMed

Zhang, Lifan; Shi, Xiaochun; Zhang, Yueqiu; Zhang, Yao; Huo, Feifei; Zhou, Baotong; Deng, Guohua; Liu, Xiaoqing

2017-08-10

T-SPOT.TB didn't perform a perfect diagnosis for active tuberculosis (ATB), and some factors may influence the results. We did this study to evaluate possible factors associated with the sensitivity and specificity of T-SPOT.TB, and the diagnostic parameters under varied conditions. Patients with suspected ATB were enrolled prospectively. Influencing factors of the sensitivity and specificity of T-SPOT.TB were evaluated using logistic regression models. Sensitivity, specificity, predictive values (PV), and likelihood ratios (LR) were calculated with consideration of relevant factors. Of the 865 participants, 205 (23.7%) had ATB, including 58 (28.3%) microbiologically confirmed TB and 147 (71.7%) clinically diagnosed TB. 615 (71.7%) were non-TB. 45 (5.2%) cases were clinically indeterminate and excluded from the final analysis. In multivariate analysis, serous effusion was the only independent risk factor related to lower sensitivity (OR = 0.39, 95% CI: 0.18-0.81) among patients with ATB. Among non-TB patients, age, TB history, immunosuppressive agents/glucocorticoid treatment and lymphocyte count were the independent risk factors related to specificity of T-SPOT.TB. Sensitivity, specificity, PV+, PV-, LR+ and LR- of T-SPOT.TB for diagnosis of ATB were 78.5%, 74.1%, 50.3%, 91.2%, 3.0 and 0.3, respectively. This study suggests that influencing factors of sensitivity and specificity of T-SPOT.TB should be considered for interpretation of T-SPOT.TB results.

Identification of a Taraxacum brevicorniculatum rubber elongation factor protein that is localized on rubber particles and promotes rubber biosynthesis.

PubMed

Laibach, Natalie; Hillebrand, Andrea; Twyman, Richard M; Prüfer, Dirk; Schulze Gronover, Christian

2015-05-01

Two protein families required for rubber biosynthesis in Taraxacum brevicorniculatum have recently been characterized, namely the cis-prenyltransferases (TbCPTs) and the small rubber particle proteins (TbSRPPs). The latter were shown to be the most abundant proteins on rubber particles, where rubber biosynthesis takes place. Here we identified a protein designated T. brevicorniculatum rubber elongation factor (TbREF) by using mass spectrometry to analyze rubber particle proteins. TbREF is homologous to the TbSRPPs but has a molecular mass that is atypical for the family. The promoter was shown to be active in laticifers, and the protein itself was localized on the rubber particle surface. In TbREF-silenced plants generated by RNA interference, the rubber content was significantly reduced, correlating with lower TbCPT protein levels and less TbCPT activity in the latex. However, the molecular mass of the rubber was not affected by TbREF silencing. The colloidal stability of rubber particles isolated from TbREF-silenced plants was also unchanged. This was not surprising because TbREF depletion did not affect the abundance of TbSRPPs, which are required for rubber particle stability. Our findings suggest that TbREF is an important component of the rubber biosynthesis machinery in T. brevicorniculatum, and may play a role in rubber particle biogenesis and influence rubber production. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

Multicenter study of QuantiFERON®-TB Gold Plus in patients with active tuberculosis.

PubMed

Horne, D J; Jones, B E; Kamada, A; Fukushima, K; Winthrop, K L; Siegel, S A R; Kovacs, A; Anthony, P; Meekin, K A; Bhat, S; Kerndt, P; Chang, A; Koelle, D M; Narita, M

2018-06-01

QuantiFERON®-TB Gold Plus (QFT-Plus), recently approved for use in the United States, is a new-generation QuantiFERON assay that differs from its predecessors in that it uses an additional antigen tube containing peptides to elicit both CD8+ and CD4+ T-lymphocyte responses. To assess the sensitivity of QFT-Plus compared with QuantiFERON®-TB Gold In-Tube (QFT-GIT) in participants with active TB. Adult patients with active TB at three US and two Japanese sites were eligible for this study if they had culture-confirmed TB and were either untreated or had received 14 days of anti-tuberculosis treatment. We enrolled 164 participants, nine of whom had indeterminate results. Excluding indeterminate values, there were 150 QFT-GIT-positive results among 159 tests and 146 QFT-Plus-positive results among 157 tests, with sensitivities of respectively 94.3% (95%CI 89.5-97.4) and 93.02% (95%CI 87.8-96.5%). The estimated sensitivities for the two tests were not significantly different (P = 0.16). Overall test agreement was 98.7%, with a κ statistic of 0.89 (95%CI 0.75-1.00). In this multisite study, we found that QFT-Plus had similar sensitivity to QFT-GIT in adult patients with active TB.

TB tracer teams in South Africa: knowledge, practices and challenges of tracing TB patients to improve adherence.

PubMed

Bristow, Claire C; Podewils, Laura Jean; Bronner, Liza Ellen; Bantubani, Nonkqubela; Walt, Martie van der; Peters, Annatjie; Mametja, David

2013-09-04

In 2008-2009 the South African National Tuberculosis (TB) Program (NTP) implemented a national pilot project, the TB Tracer Project, aiming to decrease default rates and improve patient outcomes. The current study aimed to inform the NTP by describing the knowledge, attitudes, and practices of TB program personnel involved with tracing activities. A self-administered written questionnaire was sent to TB staff, managers and tracer team leaders to assess basic TB knowledge, attitudes and practices. Descriptive statistics were used to summarize results and the chi-squared statistic was used to compare responses of staff at facilities that participated in the TB Tracer Project (tracer) and those that followed standard NTP care (non-tracer). Of 560 total questionnaires distributed, 270 were completed and returned (response rate 48%). Total TB knowledge ranged from 70.8-86.3% correct across all response groups. However, just over half (range 50-59.3%) of each respondent group was able to correctly identify the four components of a DOT encounter. A patient no longer feeling sick was cited by 72.1% of respondents as the reason patients fail to adhere to treatment. Tracer teams were viewed as an effective means to get patients to return to treatment by 96.3% of health facility level respondents. Tracer team leaders reported concerns including lack of logistical support (41.7%), insufficient physical safety precautions (41.7%), and inadequate protection from contracting TB (39.1%). Upon patients returning to treatment at the clinic, facilities included in the TB Tracer Project were significantly more likely to discuss alternate DOTS arrangements than non-tracer facilities (79.2 vs. 66.4%, p = 0.03). This study identified key components of knowledge, attitudes, and practices regarding TB patient tracing activities in South Africa. Educating patients on the essential need to complete treatment irrespective of clinical symptoms may help improve treatment adherence. Future scale-up and integration of TB tracing activities as part of standard TB management should include provisions for standardized training of personnel on the critical elements of DOTS, and for ensuring appropriate supervision, logistical support, and physical safety and TB transmission protection of tracing teams.

Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9.

PubMed

Ordonez, Alvaro A; Tasneen, Rokeya; Pokkali, Supriya; Xu, Ziyue; Converse, Paul J; Klunk, Mariah H; Mollura, Daniel J; Nuermberger, Eric L; Jain, Sanjay K

2016-07-01

Cavitation is a key pathological feature of human tuberculosis (TB), and is a well-recognized risk factor for transmission of infection, relapse after treatment and the emergence of drug resistance. Despite intense interest in the mechanisms underlying cavitation and its negative impact on treatment outcomes, there has been limited study of this phenomenon, owing in large part to the limitations of existing animal models. Although cavitation does not occur in conventional mouse strains after infection with Mycobacterium tuberculosis, cavitary lung lesions have occasionally been observed in C3HeB/FeJ mice. However, to date, there has been no demonstration that cavitation can be produced consistently enough to support C3HeB/FeJ mice as a new and useful model of cavitary TB. We utilized serial computed tomography (CT) imaging to detect pulmonary cavitation in C3HeB/FeJ mice after aerosol infection with M. tuberculosis Post-mortem analyses were performed to characterize lung lesions and to localize matrix metalloproteinases (MMPs) previously implicated in cavitary TB in situ A total of 47-61% of infected mice developed cavities during primary disease or relapse after non-curative treatments. Key pathological features of human TB, including simultaneous presence of multiple pathologies, were noted in lung tissues. Optical imaging demonstrated increased MMP activity in TB lesions and MMP-9 was significantly expressed in cavitary lesions. Tissue MMP-9 activity could be abrogated by specific inhibitors. In situ, three-dimensional analyses of cavitary lesions demonstrated that 22.06% of CD11b+ signal colocalized with MMP-9. C3HeB/FeJ mice represent a reliable, economical and tractable model of cavitary TB, with key similarities to human TB. This model should provide an excellent tool to better understand the pathogenesis of cavitation and its effects on TB treatments. © 2016. Published by The Company of Biologists Ltd.

Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9

PubMed Central

Ordonez, Alvaro A.; Tasneen, Rokeya; Pokkali, Supriya; Xu, Ziyue; Converse, Paul J.; Klunk, Mariah H.; Mollura, Daniel J.; Nuermberger, Eric L.

2016-01-01

ABSTRACT Cavitation is a key pathological feature of human tuberculosis (TB), and is a well-recognized risk factor for transmission of infection, relapse after treatment and the emergence of drug resistance. Despite intense interest in the mechanisms underlying cavitation and its negative impact on treatment outcomes, there has been limited study of this phenomenon, owing in large part to the limitations of existing animal models. Although cavitation does not occur in conventional mouse strains after infection with Mycobacterium tuberculosis, cavitary lung lesions have occasionally been observed in C3HeB/FeJ mice. However, to date, there has been no demonstration that cavitation can be produced consistently enough to support C3HeB/FeJ mice as a new and useful model of cavitary TB. We utilized serial computed tomography (CT) imaging to detect pulmonary cavitation in C3HeB/FeJ mice after aerosol infection with M. tuberculosis. Post-mortem analyses were performed to characterize lung lesions and to localize matrix metalloproteinases (MMPs) previously implicated in cavitary TB in situ. A total of 47-61% of infected mice developed cavities during primary disease or relapse after non-curative treatments. Key pathological features of human TB, including simultaneous presence of multiple pathologies, were noted in lung tissues. Optical imaging demonstrated increased MMP activity in TB lesions and MMP-9 was significantly expressed in cavitary lesions. Tissue MMP-9 activity could be abrogated by specific inhibitors. In situ, three-dimensional analyses of cavitary lesions demonstrated that 22.06% of CD11b+ signal colocalized with MMP-9. C3HeB/FeJ mice represent a reliable, economical and tractable model of cavitary TB, with key similarities to human TB. This model should provide an excellent tool to better understand the pathogenesis of cavitation and its effects on TB treatments. PMID:27482816

The impact of migration on tuberculosis epidemiology and control in high-income countries: a review.

PubMed

Pareek, Manish; Greenaway, Christina; Noori, Teymur; Munoz, Jose; Zenner, Dominik

2016-03-23

Tuberculosis (TB) causes significant morbidity and mortality in high-income countries with foreign-born individuals bearing a disproportionate burden of the overall TB case burden in these countries. In this review of tuberculosis and migration we discuss the impact of migration on the epidemiology of TB in low burden countries, describe the various screening strategies to address this issue, review the yield and cost-effectiveness of these programs and describe the gaps in knowledge as well as possible future solutions.The reasons for the TB burden in the migrant population are likely to be the reactivation of remotely-acquired latent tuberculosis infection (LTBI) following migration from low/intermediate-income high TB burden settings to high-income, low TB burden countries.TB control in high-income countries has historically focused on the early identification and treatment of active TB with accompanying contact-tracing. In the face of the TB case-load in migrant populations, however, there is ongoing discussion about how best to identify TB in migrant populations. In general, countries have generally focused on two methods: identification of active TB (either at/post-arrival or increasingly pre-arrival in countries of origin) and secondly, conditionally supported by WHO guidance, through identifying LTBI in migrants from high TB burden countries. Although health-economic analyses have shown that TB control in high income settings would benefit from providing targeted LTBI screening and treatment to certain migrants from high TB burden countries, implementation issues and barriers such as sub-optimal treatment completion will need to be addressed to ensure program efficacy.

Nuclear pore complex evolution: a trypanosome Mlp analogue functions in chromosomal segregation but lacks transcriptional barrier activity

PubMed Central

Holden, Jennifer M.; Koreny, Ludek; Obado, Samson; Ratushny, Alexander V.; Chen, Wei-Ming; Chiang, Jung-Hsien; Kelly, Steven; Chait, Brian T.; Aitchison, John D.; Rout, Michael P.; Field, Mark C.

2014-01-01

The nuclear pore complex (NPC) has dual roles in nucleocytoplasmic transport and chromatin organization. In many eukaryotes the coiled-coil Mlp/Tpr proteins of the NPC nuclear basket have specific functions in interactions with chromatin and defining specialized regions of active transcription, whereas Mlp2 associates with the mitotic spindle/NPC in a cell cycle–dependent manner. We previously identified two putative Mlp-related proteins in African trypanosomes, TbNup110 and TbNup92, the latter of which associates with the spindle. We now provide evidence for independent ancestry for TbNup92/TbNup110 and Mlp/Tpr proteins. However, TbNup92 is required for correct chromosome segregation, with knockout cells exhibiting microaneuploidy and lowered fidelity of telomere segregation. Further, TbNup92 is intimately associated with the mitotic spindle and spindle anchor site but apparently has minimal roles in control of gene transcription, indicating that TbNup92 lacks major barrier activity. TbNup92 therefore acts as a functional analogue of Mlp/Tpr proteins, and, together with the lamina analogue NUP-1, represents a cohort of novel proteins operating at the nuclear periphery of trypanosomes, uncovering complex evolutionary trajectories for the NPC and nuclear lamina. PMID:24600046

Perspectives for Developing New Tuberculosis Vaccines Derived from the Pathogenesis of Tuberculosis: I. Basic Principles, II. Preclinical Testing, and III. Clinical Testing

PubMed Central

Dannenberg, Arthur M.; Dey, Bappaditya

2013-01-01

Part I. Basic Principles. TB vaccines cannot prevent establishment of the infection. They can only prevent an early pulmonary tubercle from developing into clinical disease. A more effective new vaccine should optimize both cell-mediated immunity (CMI) and delayed-type hypersensitivity (DTH) better than any existing vaccine. The rabbit is the only laboratory animal in which all aspects of the human disease can be reproduced: namely, the prevention of most primary tubercles, the arrestment of most primary tubercles, the formation of the tubercle’s solid caseous center, the liquefaction of this center, the formation of cavities and the bronchial spread of the disease. In liquefied caseum, virulent tubercle bacilli can multiply extracellularly, especially in the liquefied caseum next to the inner wall of a cavity where oxygen is plentiful. The bacilli in liquefied caseum cannot be reached by the increased number of activated macrophages produced by TB vaccines. Therefore, new TB vaccines will have little or no effect on the extracellular bacillary growth within liquefied caseum. TB vaccines can only increase the host’s ability to stop the development of new TB lesions that arise from the bronchial spread of tubercle bacilli from the cavity to other parts of the lung. Therefore, effective TB vaccines do not prevent the reactivation of latent TB. Such vaccines only control (or reduce) the number of metastatic lesions that result after the primary TB lesion was reactivated by the liquefaction process. (Note: the large number of tubercle bacilli growing extracellularly in liquefied caseum gives rise to mutations that enable antimicrobial resistance—which is a major reason why TB still exists today). Part II. Preclinical Testing. The counting of grossly visible tubercles in the lungs of rabbits after the inhalation of virulent human-type tubercle bacilli is the most pertinent preclinical method to assess the efficacy of new TB vaccines (because an effective vaccine will stop the growth of developing tubercles before while they are still microscopic in size). Unfortunately, rabbits are rarely used in preclinical vaccine trials, despite their relative ease of handling and human-like response to this infection. Mice do not generate an effective DTH response, and guinea pigs do not generate an effective CMI response. Only the rabbits and most humans can establish the proper amount of DTH and CMI that is necessary to contain this infection. Therefore, rabbits should be included in all pre-clinical testing of new TB vaccines. New drugs (and/or immunological procedures) to reduce liquefaction and cavity formation are urgently needed. A simple intradermal way to select such drugs or procedures is described herein. Part III. Clinical Testing. Vaccine trials would be much more precise if the variations in human populations (listed herein) were taken into consideration. BCG and successful new TB vaccines should always increase host resistance to TB in naive subjects. This is a basic immunological principle. The efficacies of new and old TB vaccines are often not recognized, because these variations were not identified in the populations evaluated. PMID:26343850

Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis.

PubMed

van Rijn, S P; Zuur, M A; van Altena, R; Akkerman, O W; Proost, J H; de Lange, W C M; Kerstjens, H A M; Touw, D J; van der Werf, T S; Kosterink, J G W; Alffenaar, J W C

2017-04-01

Ertapenem is a broad-spectrum carbapenem antibiotic whose activity against Mycobacterium tuberculosis is being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40% T MIC ). To assess the 40% T MIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [AUC 0-24, fit values] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation ( n = 1,000) was used to evaluate limited sampling strategies. Additionally, the 40% T MIC with the free fraction ( f 40% T MIC ) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) in MDR-TB patients by 6.8% (range, -17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h ( r 2 = 0.78, mean prediction error = -0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, -15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimum f 40% T MIC would have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients. Copyright © 2017 American Society for Microbiology.

Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis

PubMed Central

van Rijn, S. P.; Zuur, M. A.; van Altena, R.; Akkerman, O. W.; Proost, J. H.; de Lange, W. C. M.; Kerstjens, H. A. M.; Touw, D. J.; van der Werf, T. S.; Kosterink, J. G. W.

2017-01-01

ABSTRACT Ertapenem is a broad-spectrum carbapenem antibiotic whose activity against Mycobacterium tuberculosis is being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40% TMIC). To assess the 40% TMIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [AUC0–24, fit values] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation (n = 1,000) was used to evaluate limited sampling strategies. Additionally, the 40% TMIC with the free fraction (f 40% TMIC) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC0–24) in MDR-TB patients by 6.8% (range, −17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h (r2 = 0.78, mean prediction error = −0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, −15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimum f 40% TMIC would have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients. PMID:28137814

EFIS lecture. Immune response to tuberculosis: How to control the most successful pathogen on earth.

PubMed

Kaufmann, Stefan H E

2016-07-01

Tuberculosis (TB) remains a major health threat and general agreement exists that better control measures are needed. These include better diagnostics, drugs and vaccines. In particular, vaccines will be critical for better TB control. Based on knowledge about protective immunity against TB, a vaccine was created, VPM1002, which shows high protective efficacy and safety in experimental animal models. The vaccine has proven safe and immunogenic in human adults and neonates and is currently assessed in clinical trials in the context of HIV exposure. As a next step, a phase III efficacy trial in adults and a phase IIb efficacy trial in neonates are being planned. Biosignatures that differentially diagnose TB disease versus latent infection with high sensitivity and specificity have been designed. Most recently, a prognostic biosignature which predicts progression from latent infection to active TB has been identified. Biosignatures are not only of great value for improved diagnosis and prognosis of TB, they can also provide guidelines for better understanding of molecular mechanisms underlying disease. Accordingly, distinct biomarkers of diagnostic and prognostic value but of unknown biological function are being characterized functionally. In this way, deeper insights have been obtained on the role of type I interferon and of neutrophils in TB in experimental animal models of TB. In conclusion, clinical and basic research further supported by computational biology can complement each other in the pursuit of knowledge-based development of improved intervention measures for TB control. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Tuberculosis vaccine development at a divide.

PubMed

Kaufmann, Stefan H E

2014-05-01

Tuberculosis (TB) remains a major health threat that will only be defeated by a combination of better drugs, diagnostics and vaccines. The only licensed TB vaccine, bacille Calmette-Guérin (BCG), protects against extrapulmonary TB in infants. Novel vaccine candidates that could protect against pulmonary TB either in TB naïve or in latent TB-infected healthy individuals have been developed and are currently being assessed in clinical trials. Subunit booster vaccines are either based on viral vectors expressing TB-specific antigens or on TB-protein antigens in adjuvants. Subunit vaccines are administered on top of BCG. Replacement vaccines for BCG are recombinant viable BCG or Mycobacterium tuberculosis. Several candidates are undergoing, or will soon start, phase IIb assessment for efficacy. The first vaccine candidate, MVA85A, to complete a phase IIb trial, unfortunately failed to show protection against TB in infants. Therapeutic vaccines composed of killed mycobacterial preparations target patients with complicated TB in adjunct to drug treatment. With increasing numbers of TB vaccine candidates in clinical trials, financial, regulatory and infrastructural issues arise, which would be best tackled by a global strategy. In addition, selection of the most promising vaccine candidates for further clinical development gains increasing importance.

The Significance of Sensitive Interferon Gamma Release Assays for Diagnosis of Latent Tuberculosis Infection in Patients Receiving Tumor Necrosis Factor-α Antagonist Therapy.

PubMed

Jung, Yu Jung; Woo, Hye In; Jeon, Kyeongman; Koh, Won-Jung; Jang, Dong Kyoung; Cha, Hoon Suk; Koh, Eun Mi; Lee, Nam Yong; Kang, Eun-Suk

2015-01-01

We compared two interferon gamma release assays (IGRAs), QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, for diagnosis of latent tuberculosis infection (LTBI) in patients before and while receiving tumor necrosis factor (TNF)-α antagonist therapy. This study evaluated the significance of sensitive IGRAs for LTBI screening and monitoring. Before starting TNF-α antagonist therapy, 156 consecutive patients with rheumatic diseases were screened for LTBI using QFT-GIT and T-SPOT.TB tests. According to our study protocol, QFT-GIT-positive patients received LTBI treatment. Patients positive by any IGRAs were subjected to follow-up IGRA tests after completing LTBI-treatment and/or during TNF-α antagonist therapy. At the initial LTBI screening, 45 (28.9%) and 70 (44.9%) patients were positive by QFT-GIT and T-SPOT.TB, respectively. The agreement rate between IGRA results was 78.8% (k = 0.56; 95% confidence interval [95% CI] = 0.43 to 0.68). Of 29 patients who were positive only by T-SPOT.TB in the initial screening, 83% (19/23) were persistently positive by T-SPOT.TB, while QFT-GIT testing showed that 36% (9/25) had conversion during TNF-α antagonist therapy. By the end of the follow-up period (218 to 1,264 days), four patients (4/137, 2.9%) developed active tuberculosis (TB) diseases during receiving TNF-α antagonist therapy. Among them, one was Q-T+, one was Q+T-, and the remaining two were Q-T- at the initial screening (Q, QuantiFERON-TB Gold In-Tube; T, T-SPOT.TB; +, positive; -, negative). Two (2/4, 50%) patients with TB reactivation had at least one prior risk factor consistent with previous TB infection. This study demonstrated the need to capitalize on sensitive IGRAs to monitor for LTBI in at-risk patients for a more sensitive diagnosis in countries with an intermediate TB burden.

Mapping sites of high TB transmission risk: Integrating the shared air and social behaviour of TB cases and adolescents in a South African township.

PubMed

Patterson, Benjamin; Morrow, Carl D; Kohls, Daniel; Deignan, Caroline; Ginsburg, Samuel; Wood, Robin

2017-04-01

Tuberculosis remains a major public health problem in poverty-stricken areas of the world. Communal gathering places account for the majority of TB transmission in high burden settings. To investigate the social behaviour patterns of individuals who have developed TB disease and adolescents at risk of infection. To develop a cheap and effective method to locate transmission hot spots in high burden communities. Portable, combined CO 2 /GIS monitors and location diaries were given to individuals from a South African township. The three groups: newly diagnosed TB patients, recently treated TB patients and adolescents recorded their activities over a median of two days. Rebreathed air volumes (RAVs) at all GIS locations were calculated from CO 2 levels using the Rudnick-Milton variant of the Wells-Riley TB transmission model. Hot spot analysis was performed to determine the communal buildings which correspond to spatially clustered high RAVs. Analysis of diaries found that the adolescent group spent greater time in congregate settings compared with the other two groups driven by time spent in school/work (new TB: 1%, recent TB: 8%, and adolescents: 23%). Adolescents also changed their location more frequently (9.0, 6.0, 14.3 changes per day; p<0.001). The RAVs reflected this divergence between the groups (44, 40, 127l; p<0.001). Communal buildings associated with high RAVs were found to be a clinic, two schools and a library. Hot spot analysis revealed the most intense clustering of high RAVs at a community school. Our study demonstrates a new methodology to uncover TB transmission hot spots using a technique that avoids the need to pre-select locations. Investigation of a South African township highlighted the high risk potential of schools and high risk social behaviour of adolescents. Consequently the targeting of transmission reduction strategies to schools may prove highly efficacious in high burden settings. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

A survey to assess the extent of public-private mix DOTS in the management of tuberculosis in Zambia

PubMed Central

Kapata, Nathan; Maboshe, Mwendaweli; Michelo, Charles; Babaniyi, Olusegun

2015-01-01

Background Involving all relevant healthcare providers in tuberculosis (TB) management through public-private mix (PPM) approaches is a vital element in the World Health Organization's (WHO) Stop TB Strategy. The control of TB in Zambia is mainly done in the public health sector, despite the high overall incidence rates. Aim We conducted a survey to determine the extent of private-sector capacity, participation, practices and adherence to national guidelines in the control of TB. Setting This survey was done in the year 2012 in 157 facilities in three provinces of Zambia where approximately 85% of the country's private health facilities are found. Methods We used a structured questionnaire to interview the heads of private health facilities to assess the participation of the private health sector in TB diagnosis, management and prevention activities. Results Out of 157 facilities surveyed, 40.5% were from the Copperbelt, 4.4% from Central province and 55.1% from Lusaka province. Only 23.8% of the facilities were able to provide full diagnosis and management of TB patients. Although 47.4% of the facilities reported that they do notify their cases to the National TB control programme, the majority (62.7%) of these facilities did not show evidence of notifications. Conclusion Our results show that the majority of the facilities that diagnose and manage TB in the private sector do not report their TB activities to the National TB Control Programme (NTP). There is a need for the NTP to improve collaboration with the private sector with respect to TB control activities and PPM for Directly Observed Treatment, Short Course (DOTS). PMID:26245591

Multifunctional G-Rich and RRM-Containing Domains of TbRGG2 Perform Separate yet Essential Functions in Trypanosome RNA Editing

PubMed Central

Foda, Bardees M.; Downey, Kurtis M.; Fisk, John C.

2012-01-01

Efficient editing of Trypanosoma brucei mitochondrial RNAs involves the actions of multiple accessory factors. T. brucei RGG2 (TbRGG2) is an essential protein crucial for initiation and 3′-to-5′ progression of editing. TbRGG2 comprises an N-terminal G-rich region containing GWG and RG repeats and a C-terminal RNA recognition motif (RRM)-containing domain. Here, we perform in vitro and in vivo separation-of-function studies to interrogate the mechanism of TbRGG2 action in RNA editing. TbRGG2 preferentially binds preedited mRNA in vitro with high affinity attributable to its G-rich region. RNA-annealing and -melting activities are separable, carried out primarily by the G-rich and RRM domains, respectively. In vivo, the G-rich domain partially complements TbRGG2 knockdown, but the RRM domain is also required. Notably, TbRGG2's RNA-melting activity is dispensable for RNA editing in vivo. Interactions between TbRGG2 and MRB1 complex proteins are mediated by both G-rich and RRM-containing domains, depending on the binding partner. Overall, our results are consistent with a model in which the high-affinity RNA binding and RNA-annealing activities of the G-rich domain are essential for RNA editing in vivo. The RRM domain may have key functions involving interactions with the MRB1 complex and/or regulation of the activities of the G-rich domain. PMID:22798390

Tuberculosis in a South African prison – a transmission modelling analysis

PubMed Central

Johnstone-Robertson, Simon; Lawn, Stephen D; Welte, Alex; Bekker, Linda-Gail; Wood, Robin

2015-01-01

Background Prisons are recognised internationally as institutions with very high tuberculosis (TB) burdens where transmission is predominantly determined by contact between infectious and susceptible prisoners. A recent South African court case described the conditions under which prisoners awaiting trial were kept. With the use of these data, a mathematical model was developed to explore the interactions between incarceration conditions and TB control measures. Methods Cell dimensions, cell occupancy, lock-up time, TB incidence and treatment delays were derived from court evidence and judicial reports. Using the Wells-Riley equation and probability analyses of contact between prisoners, we estimated the current TB transmission probability within prison cells, and estimated transmission probabilities of improved levels of case finding in combination with implementation of national and international minimum standards for incarceration. Results Levels of overcrowding (230%) in communal cells and poor TB case finding result in annual TB transmission risks of 90% per annum. Implementing current national or international cell occupancy recommendations would reduce TB transmission probabilities by 30% and 50%, respectively. Improved passive case finding, modest ventilation increase or decreased lock-up time would minimally impact on transmission if introduced individually. However, active case finding together with implementation of minimum national and international standards of incarceration could reduce transmission by 50% and 94%, respectively. Conclusions Current conditions of detention for awaiting-trial prisoners are highly conducive for spread of drug-sensitive and drug-resistant TB. Combinations of simple well-established scientific control measures should be implemented urgently. PMID:22272961

Digital health for the End TB Strategy: developing priority products and making them work.

PubMed

Falzon, Dennis; Timimi, Hazim; Kurosinski, Pascal; Migliori, Giovanni Battista; Van Gemert, Wayne; Denkinger, Claudia; Isaacs, Chris; Story, Alistair; Garfein, Richard S; do Valle Bastos, Luis Gustavo; Yassin, Mohammed A; Rusovich, Valiantsin; Skrahina, Alena; Van Hoi, Le; Broger, Tobias; Abubakar, Ibrahim; Hayward, Andrew; Thomas, Bruce V; Temesgen, Zelalem; Quraishi, Subhi; von Delft, Dalene; Jaramillo, Ernesto; Weyer, Karin; Raviglione, Mario C

2016-07-01

In 2014, the World Health Organization (WHO) developed the End TB Strategy in response to a World Health Assembly Resolution requesting Member States to end the worldwide epidemic of tuberculosis (TB) by 2035. For the strategy's objectives to be realised, the next 20 years will need novel solutions to address the challenges posed by TB to health professionals, and to affected people and communities. Information and communication technology presents opportunities for innovative approaches to support TB efforts in patient care, surveillance, programme management and electronic learning. The effective application of digital health products at a large scale and their continued development need the engagement of TB patients and their caregivers, innovators, funders, policy-makers, advocacy groups, and affected communities.In April 2015, WHO established its Global Task Force on Digital Health for TB to advocate and support the development of digital health innovations in global efforts to improve TB care and prevention. We outline the group's approach to stewarding this process in alignment with the three pillars of the End TB Strategy. The supplementary material of this article includes target product profiles, as developed by early 2016, defining nine priority digital health concepts and products that are strategically positioned to enhance TB action at the country level. The content of this work is ©the authors or their employers. Design and branding are ©ERS 2016.

TB-IRIS and remodelling of the T cell compartment in highly immunosuppressed HIV+ patients with TB: the CAPRI T (ANRS-12614) study

PubMed Central

Haridas, V.; Pean, P.; Jasenosky, L.D.; Madec, Y.; Laureillard, D.; Sok, T.; Sath, S.; Borand, L.; Marcy, O.; Chan, S.; Tsitsikov, E.; Delfraissy, J.-F.; Blanc, F.-X.; Goldfeld, A.E.

2015-01-01

Objective To investigate the impact of tuberculosis (TB)-associated immune reconstitution syndrome (IRIS) upon immunological recovery and the T cell compartment after initiation of TB and antiretroviral therapy (ART). Design and methods We prospectively evaluated T cell immunophenotypes by flow cytometry and cytokines by Luminex assays in a subset (n=154) of highly immunosuppressed HIV+ patients with TB from the CAMELIA randomized clinical trial. We compared findings from patients who developed TB-IRIS to findings from patients who did not develop TB-IRIS. Data were evaluated with mixed effect linear regression, Kaplan-Meier estimates, and Wilcoxon rank sum tests, and q-values were calculated to control for multiple comparisons. Results Development of TB-IRIS was associated with significantly greater pre-ART frequencies of HLA-DR+CD45RO+CD4+, CCR5+CD4+, OX40+CD4+, and Fas+ effector memory (EM) CD8+ T cells, and significantly elevated levels of plasma IL-6, IL-1β, IL-8, and IL-10 and viral load. Post-ART initiation, EM CD4+ and Fas+ EM CD4+ T cell frequencies significantly expanded, and central memory (CM) CD4+ T cell frequencies significantly contracted in patients who experienced TB-IRIS. By week 34 post-TB treatment initiation, EM/CM CD4+ T cell ratios were markedly higher in TB-IRIS versus non-TB-IRIS patients. Conclusions A distinct pattern of pre-ART T cell and cytokine markers appear to poise the immune response to develop TB-IRIS. Experience of TB-IRIS is then associated with long-term remodeling of the CD4+ T cell memory compartment towards an EM-dominated phenotype. We speculate that these pre- and post-ART TB-IRIS-associated immune parameters may contribute to superior immune control of TB/HIV co-infection and better clinical outcome. PMID:25486415

The Activity of a Hexameric M17 Metallo-Aminopeptidase Is Associated With Survival of Mycobacterium tuberculosis

PubMed Central

Correa, Andre F.; Bastos, Izabela M. D.; Neves, David; Kipnis, Andre; Junqueira-Kipnis, Ana P.; de Santana, Jaime M.

2017-01-01

Mycobacterium tuberculosis is one of the most prevalent human pathogens causing millions of deaths in the last years. Moreover, tuberculosis (TB) treatment has become increasingly challenging owing to the emergence of multidrug resistant M. tuberculosis strains. Thus, there is an immediate need for the development of new anti-TB drugs. Proteases appear to be a promising approach and may lead to shortened and effective treatments for drug-resistant TB. Although the M. tuberculosis genome predicts more than 100 genes encoding proteases, only a few of them have been studied. Aminopeptidases constitute a set of proteases that selectively remove amino acids from the N-terminus of proteins and peptides and may act as virulence factors, essential for survival and maintenance of many microbial pathogens. Here, we characterized a leucine aminopeptidase of M. tuberculosis (MtLAP) as a cytosolic oligomeric metallo-aminopeptidase. Molecular and enzymatic properties lead us to classify MtLAP as a typical member of the peptidase family M17. Furthermore, the aminopeptidase inhibitor bestatin strongly inhibited MtLAP activity, in vitro M. tuberculosis growth and macrophage infection. In murine model of TB, bestatin treatment reduced bacterial burden and lesion in the lungs of infected mice. Thus, our data suggest that MtLAP participates in important metabolic pathways of M. tuberculosis necessary for its survival and virulence and consequently may be a promising target for new anti-TB drugs. PMID:28396657

[PECULIARITY OF NATIONAL TUBERCULOSIS PROGRAM, JAPAN--Public-Private Mix from the Very Beginning, and Provision of X-ray Apparatus in Most General Practitioner's Clinics].

PubMed

Shimao, Tadao

2016-02-01

Modern National Tuberculosis Program (NTP) of Japan started in 1951 when Tuberculosis (TB) Control Law was legislated, and 3 major components were health examination by tuberculin skin test (TST) and miniature X-ray, BCG vaccination and extensive use of modern TB treatment. As to the treatment program, Japan introduced Public-Private Mix (PPM) from the very beginning, and major reasons why PPM was adopted are (1) TB was then highly prevalent (Table 1), (2) TB sanatoria where many specialists are working are located in remote inconvenient places due to stigma against TB, (3) health centers (HCs) in Japan are working exclusively on prophylactic activities, and minor exceptions are treatment of sexually transmitted diseases and artificial pneumothorax for TB cases, however, as it covers on the average 100,000 population, access is not so easy in rural area, (4) Out-patients clinics mainly operated by general practitioners (GPs) are located throughout Japan, and the access is easy. Methods of TB treatment was developing rapidly in early 1950s, however, in 1952, as shown in Table 2, artificial pneumothorax and peritoneum were still used in many cases, and to fix the dosage of refill air, fluoroscopy was needed. Hence, GPs treating TB under TB Control Law had to be equipped with X-ray apparatus. To maintain the quality of TB treatment, "Criteria for TB treatment" was provided and revised taking into consideration the progress in TB treatment. If applied methods of treatment fit with the above criteria, public support is made for the cost of TB treatment. To discuss the applied treatment, TB Advisory Committee was set in each HC, composing of 5 members, director of HC, 2 TB specialists and 2 doctors recommended by the local medical association. In 1953, the first TB prevalence survey using stratified random sampling method was carried out, and the prevalence of TB requiring treatment was estimated at 3.4%, and only 21% of found cases knew their own disease, and more than half of all TB were found above 30 years of age. Based on these results, mass screening was expanded to cover whole population in 1955, and since 1957, cost of mass screening and BCG vaccination was covered 100% by public fund. Unified TB registration system covering whole Japan was introduced in 1961, and in the same year, national government subsidy for the hospitalization of infectious TB cases was raised from 50% to 80%. Hence, Japan succeeded to organize PPM system in TB care, and with 10% annual decline of TB, in 1975, Japan moved into the TB middle prevalence country.

Discovery and Biochemical Characterization of PlyP56, PlyN74, and PlyTB40—Bacillus Specific Endolysins

PubMed Central

Etobayeva, Irina; Linden, Sara B.; Alem, Farhang; Rizkalla, Lucas; Temple, Louise; Hakami, Ramin M.

2018-01-01

Three Bacillus bacteriophage-derived endolysins, designated PlyP56, PlyN74, and PlyTB40, were identified, cloned, purified, and characterized for their antimicrobial properties. Sequence alignment reveals these endolysins have an N-terminal enzymatically active domain (EAD) linked to a C-terminal cell wall binding domain (CBD). PlyP56 has a Peptidase_M15_4/VanY superfamily EAD with a conserved metal binding motif and displays biological dependence on divalent ions for activity. In contrast, PlyN74 and PlyTB40 have T7 lysozyme-type Amidase_2 and carboxypeptidase T-type Amidase_3 EADs, respectively, which are members of the MurNAc-LAA superfamily, but are not homologs and thus do not have a shared protein fold. All three endolysins contain similar SH3-family CBDs. Although minor host range differences were noted, all three endolysins show relatively broad antimicrobial activity against members of the Bacillus cereus sensu lato group with the highest lytic activity against B. cereus ATCC 4342. Characterization studies determined the optimal lytic activity for these enzymes was at physiological pH (pH 7.0–8.0), over a broad temperature range (4–55 °C), and at low concentrations of NaCl (<50 mM). Direct comparison of lytic activity shows the PlyP56 enzyme to be twice as effective at lysing the cell wall peptidoglycan as PlyN74 or PlyTB40, suggesting PlyP56 is a good candidate for further antimicrobial development as well as bioengineering studies. PMID:29883383

PA-Tb-Cu MOF as luminescent nanoenzyme for catalytic assay of hydrogen peroxide.

PubMed

Qi, Zewan; Wang, Li; You, Qi; Chen, Yang

2017-10-15

Metal organic frameworks (MOFs) with flexible structures and components have aroused great interest in designing functional materials. In this work, we designed and made a kind of PA-Tb-Cu MOF nanoenzyme capable of emitting fluorescence for the catalytic reaction of hydrogen peroxide (H 2 O 2 ). Luminescent Tb 3+ , catalytic Cu 2+ and bridging ligand were assembled and integrated into a single material nanoenzyme. This PA-Tb-Cu MOF nanoenzyme not only possessed excellent catalytic activity comparable to horseradish peroxidase but also can real-time fluorescently indicate the concentration of H 2 O 2 as low as 0.2µM during catalysis. Luminescent PA-Tb-Cu MOF nanoenzyme did not need a common combined use of natural/artificial enzymes and chromogenic reactions for the quantification of H 2 O 2 in widely-used enzyme-catalytic reactions. The present strategy assembled directly from functional ions/molecules provides a new way for the design and development of smart, multifunctional artificial enzymes for wide applications in biocatalysis, bioassays and nano-biomedicine. Copyright © 2017 Elsevier B.V. All rights reserved.

Hit Generation in TB Drug Discovery: From Genome to Granuloma

PubMed Central

2018-01-01

Current tuberculosis (TB) drug development efforts are not sufficient to end the global TB epidemic. Recent efforts have focused on the development of whole-cell screening assays because biochemical, target-based inhibitor screens during the last two decades have not delivered new TB drugs. Mycobacterium tuberculosis (Mtb), the causative agent of TB, encounters diverse microenvironments and can be found in a variety of metabolic states in the human host. Due to the complexity and heterogeneity of Mtb infection, no single model can fully recapitulate the in vivo conditions in which Mtb is found in TB patients, and there is no single “standard” screening condition to generate hit compounds for TB drug development. However, current screening assays have become more sophisticated as researchers attempt to mirror the complexity of TB disease in the laboratory. In this review, we describe efforts using surrogates and engineered strains of Mtb to focus screens on specific targets. We explain model culture systems ranging from carbon starvation to hypoxia, and combinations thereof, designed to represent the microenvironment which Mtb encounters in the human body. We outline ongoing efforts to model Mtb infection in the lung granuloma. We assess these different models, their ability to generate hit compounds, and needs for further TB drug development, to provide direction for future TB drug discovery. PMID:29384369

A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity

PubMed Central

Sharlow, Elizabeth R.; Lyda, Todd A.; Dodson, Heidi C.; Mustata, Gabriela; Morris, Meredith T.; Leimgruber, Stephanie S.; Lee, Kuo-Hsiung; Kashiwada, Yoshiki; Close, David; Lazo, John S.; Morris, James C.

2010-01-01

Background The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the γ-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay. Methodology/Principal Findings Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were ∼20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03≤EC50<3 µM) with parasite specificity of the compounds being demonstrated using insect stage T. brucei parasites, Leishmania promastigotes, and mammalian cell lines. Analysis of two structurally related compounds, ebselen and SID 17387000, revealed that both were mixed inhibitors of TbHK1 with respect to ATP. Additionally, both compounds inhibited parasite lysate-derived HK activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics. Conclusions/Significance The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome. PMID:20405000

Diabetes mellitus: an important risk factor for reactivation of tuberculosis.

PubMed

Solá, Ernesto; Rivera, Carmen; Mangual, Michelle; Martinez, José; Rivera, Kelvin; Fernandez, Ricardo

2016-01-01

Diabetes mellitus was identified as a risk factor for developing tuberculosis (TB) infection, and relapse after therapy. The risk of acquiring TB is described as comparable to that of HIV population. The fact that diabetics are 3× times more prone to develop pulmonary TB than nondiabetics cannot be overlooked. With DM recognized as global epidemic, and TB affecting one-third of the world population, physicians must remain vigilant. We present a 45-year-old woman born in Dominican Republic (DR), with 10-year history of T2DM treated with metformin, arrived to our Urgency Room complaining of dry cough for the past 3months. Interview unveiled unintentional 15lbs weight loss, night sweats, occasional unquantified fever, and general malaise but denied bloody sputum. She traveled to DR 2years before, with no known ill exposure. Physical examination showed a thin body habitus, otherwise well appearing woman with stable vital signs, presenting solely right middle lung field ronchi. LDH, ESR, hsCRP and Hg A1C were elevated. Imaging revealed a right middle lobe cavitation. Sputum for AFB disclosed active pulmonary TB. Our case portrays that the consideration of TB as differential diagnosis in diabetics should be exercised with the same strength, as it is undertaken during the evaluation of HIV patients with lung cavitation. Inability to recognize TB will endanger the patient, hospital dwellers and staff, and perpetuate this global public health menace. Diabetes mellitus should be considered an important risk factor for the reactivation of pulmonary tuberculosis.High clinical suspicious should be taken into consideration as radiological findings for pulmonary tuberculosis in patients with diabetes mellitus may be atypical, involving middle and lower lobes.Inability to recognize pulmonary tuberculosis will endanger the patient, hospital dwellers and staff, and perpetuate this global public health menace.

Adherence to and outcome of isoniazid chemoprophylaxis among household contact children of adults having pulmonary tuberculosis in Alexandria, Egypt.

PubMed

Mohamed, Aida M

2012-08-01

Current international guidelines recommend 6-9 months of isoniazid (INH) preventive chemotherapy to prevent the development of active tuberculosis (TB) in susceptible children exposed to Mycobacterium tuberculosis. However, this is dependent on good adherence, as shown by previous studies. This study was conducted to describe the outcome of screening of contact children aged 5 years or less with household exposure to an adult pulmonary TB index case to determine the prevalence and possible risk factors of infection among contact children and to determine the extent and outcome of adherence of contact children to unsupervised INH chemoprophylaxis for 6 months. A descriptive facility-based cross-sectional study was conducted from March 2009 to August 2010. Research settings were three of the National TB control program chest dispensaries (primary care facilities) in Alexandria, Egypt. Facility-based TB treatment registers of the previous 3 months were used to identify all new adult pulmonary TB cases. All children aged 5 years or less living in the same house as the index cases were identified and screened for TB. The contact children were given unsupervised INH preventive chemotherapy once active TB was excluded. Adherence to and outcome of preventive chemotherapy were followed up. Preventive chemotherapy consisted of unsupervised INH monotherapy for 6 months with monthly collection of tablets from the clinic. Adherence was documented after completion of the 6-month preventive treatment period. Adherence was considered reasonable if tablets were collected for more than 4 months, poor if collected for 2-4 months, and very poor if collected for less than 2 months. (a) Prevalence of infection and disease and the possible risk factors among contacts. (b) The extent and outcome of adherence to unsupervised INH chemoprophylaxis among contact children. (c) Factors behind poor adherence. In total, 197 adult TB index cases from 187 households were identified. In all, 297 children aged 5 years or less experienced household exposure, of whom 252 (84.9%) were fully evaluated. Tuberculin test was positive in 136 of the 252 child contacts (54.0%), of whom 130 were contacts of sputum-positive patients and six were contacts of sputum-negative patients. The important risk factors for transmission of TB infection were younger age, male sex, severe malnutrition, absence of BCG vaccination, contact with a sputum-positive adult who was a source case, household overcrowding, and exposure to environmental tobacco smoke. Thirty-three children were diagnosed and treated for TB at the baseline screening and 217 received preventive INH chemotherapy. Of the children who received preventive chemotherapy, only 36 (16.6%) completed at least 4 months of unsupervised INH monotherapy. During the subsequent follow-up period, eight children developed TB (secondary attack rate for TB disease was 3.7%), of whom four received no preventive chemotherapy and four were poorly adherent. The prevalence of TB infection and clinical disease among children in household contact with adult patients is high, and risk is significantly increased because of child contact, index patients and environmental factors. Adherence to 6 months of unsupervised INH chemoprophylaxis was very poor.

Diagnosis and therapeutic approach of latent tuberculosis infection.

PubMed

Domínguez, José; Latorre, Irene; Santin, Miguel

2018-05-01

Detection and treatment of latent tuberculosis infection (LTBI) is an essential measure for tuberculosis (TB) control in low-incidence countries. However, such strategy is limited by the low predictive ability of the diagnostic tests for the development of active TB among infected people and the long-term and toxic treatment regimens. The in vitro interferon-gamma release assays are more specific and sensitive than the tuberculin skin test (TST), and enable a better selection of cases requiring treatment. Nonetheless, their capacity to predict development of TB is still poor. In addition, treatment regimens for LTBI are long, and compliance rates are low. This review discusses the use of the available diagnostic tests and the new approaches to the diagnosis of LTBI, as well as its management in different clinical scenarios. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Granzyme A as a potential biomarker of Mycobacterium tuberculosis infection and disease.

PubMed

Guggino, Giuliana; Orlando, Valentina; Cutrera, Stella; La Manna, Marco P; Di Liberto, Diana; Vanini, Valentina; Petruccioli, Elisa; Dieli, Francesco; Goletti, Delia; Caccamo, Nadia

2015-08-01

Cytotoxic molecules such as granulysin, perforin and granzymes produced by cytolytic T cells directly contribute to immune defense against tuberculosis (TB). In search for novel TB biomarkers, we have evaluated the levels of granzyme A in plasma obtained from QuantiFERON-TB Gold In tube (QFT-IT) assays from patients with active TB disease and subjects with latent TB infection (LTBI). Granzyme A serum levels in TB patients were significantly lower than values found in LTBI subjects even after subtraction of the unstimulated levels from the antigen-stimulated responses. The receiver operator characteristics (ROC) curve analysis comparing TB patients and LTBI groups, showed that at a cut-off value of granzyme A of <3.425pg/ml, the sensitivity and the specificity of the assay were 29.41% and 94.74%, respectively. Our results suggest that granzyme A could be considered another biomarker of TB, that can be used, other than IFN-γ, to discriminate between patients with active TB and LTBI subjects in a well characterized cohort of confirmed Mycobacterium tuberculosis-infected individuals. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

The Tuberculosis Cascade of Care in India's Public Sector: A Systematic Review and Meta-analysis.

PubMed

Subbaraman, Ramnath; Nathavitharana, Ruvandhi R; Satyanarayana, Srinath; Pai, Madhukar; Thomas, Beena E; Chadha, Vineet K; Rade, Kiran; Swaminathan, Soumya; Mayer, Kenneth H

2016-10-01

India has 23% of the global burden of active tuberculosis (TB) patients and 27% of the world's "missing" patients, which includes those who may not have received effective TB care and could potentially spread TB to others. The "cascade of care" is a useful model for visualizing deficiencies in case detection and retention in care, in order to prioritize interventions. The care cascade constructed in this paper focuses on the Revised National TB Control Programme (RNTCP), which treats about half of India's TB patients. We define the TB cascade as including the following patient populations: total prevalent active TB patients in India, TB patients who reach and undergo evaluation at RNTCP diagnostic facilities, patients successfully diagnosed with TB, patients who start treatment, patients retained to treatment completion, and patients who achieve 1-y recurrence-free survival. We estimate each step of the cascade for 2013 using data from two World Health Organization (WHO) reports (2014-2015), one WHO dataset (2015), and three RNTCP reports (2014-2016). In addition, we conduct three targeted systematic reviews of the scientific literature to identify 39 unique articles published from 2000-2015 that provide additional data on five indicators that help estimate different steps of the TB cascade. We construct separate care cascades for the overall population of patients with active TB and for patients with specific forms of TB-including new smear-positive, new smear-negative, retreatment smear-positive, and multidrug-resistant (MDR) TB. The WHO estimated that there were 2,700,000 (95%CI: 1,800,000-3,800,000) prevalent TB patients in India in 2013. Of these patients, we estimate that 1,938,027 (72%) TB patients were evaluated at RNTCP facilities; 1,629,906 (60%) were successfully diagnosed; 1,417,838 (53%) got registered for treatment; 1,221,764 (45%) completed treatment; and 1,049,237 (95%CI: 1,008,775-1,083,243), or 39%, of 2,700,000 TB patients achieved the optimal outcome of 1-y recurrence-free survival. The separate cascades for different forms of TB highlight different patterns of patient attrition. Pretreatment loss to follow-up of diagnosed patients and post-treatment TB recurrence were major points of attrition in the new smear-positive TB cascade. In the new smear-negative and MDR TB cascades, a substantial proportion of patients who were evaluated at RNTCP diagnostic facilities were not successfully diagnosed. Retreatment smear-positive and MDR TB patients had poorer treatment outcomes than the general TB population. Limitations of our analysis include the lack of available data on the cascade of care in the private sector and substantial uncertainty regarding the 1-y period prevalence of TB in India. Increasing case detection is critical to improving outcomes in India's TB cascade of care, especially for smear-negative and MDR TB patients. For new smear-positive patients, pretreatment loss to follow-up and post-treatment TB recurrence are considerable points of attrition that may contribute to ongoing TB transmission. Future multisite studies providing more accurate information on key steps in the public sector TB cascade and extension of this analysis to private sector patients may help to better target interventions and resources for TB control in India.

Contribution of Auger/conversion electrons to renal side effects after radionuclide therapy: preclinical comparison of (161)Tb-folate and (177)Lu-folate.

PubMed

Haller, Stephanie; Pellegrini, Giovanni; Vermeulen, Christiaan; van der Meulen, Nicholas P; Köster, Ulli; Bernhardt, Peter; Schibli, Roger; Müller, Cristina

2016-12-01

The radiolanthanide (161)Tb has, in recent years, attracted increasing interest due to its favorable characteristics for medical application. (161)Tb exhibits similar properties to the widely-used therapeutic radionuclide (177)Lu. In contrast to (177)Lu, (161)Tb yields a significant number of short-ranging Auger/conversion electrons (≤50 keV) during its decay process. (161)Tb has been shown to be more effective for tumor therapy than (177)Lu if applied using the same activity. The purpose of this study was to investigate long-term damage to the kidneys after application of (161)Tb-folate and compare it to the renal effects caused by (177)Lu-folate. Renal side effects were investigated in nude mice after the application of different activities of (161)Tb-folate (10, 20, and 30 MBq per mouse) over a period of 8 months. Renal function was monitored by the determination of (99m)Tc-DMSA uptake in the kidneys and by measuring blood urea nitrogen and creatinine levels in the plasma. Histopathological analysis was performed by scoring of the tissue damage observed in HE-stained kidney sections from euthanized mice. Due to the co-emitted Auger/conversion electrons, the mean absorbed renal dose of (161)Tb-folate (3.0 Gy/MBq) was about 24 % higher than that of (177)Lu-folate (2.3 Gy/MBq). After application of (161)Tb-folate, kidney function was reduced in a dose- and time-dependent manner, as indicated by the decreased renal uptake of (99m)Tc-DMSA and the increased levels of blood urea nitrogen and creatinine. Similar results were obtained when (177)Lu-folate was applied at the same activity. Histopathological investigations confirmed comparable renal cortical damage after application of the same activities of (161)Tb-folate and (177)Lu-folate. This was characterized by collapsed tubules and enlarged glomeruli with fibrin deposition in moderately injured kidneys and glomerulosclerosis in severely damaged kidneys. Tb-folate induced dose-dependent radionephropathy over time, but did not result in more severe damage than (177)Lu-folate when applied at the same activity. These data are an indication that Auger/conversion electrons do not exacerbate overall renal damage after application with (161)Tb-folate as compared to (177)Lu-folate, even though they result in an increased dose deposition in the renal tissue. Global toxicity affecting other tissues than kidneys remains to be investigated after (161)Tb-based therapy, however.

Diabetes increases the risk of recent-transmission tuberculosis in household contacts in São Paulo, Brazil.

PubMed

Rajan, J V; Ferrazoli, L; Waldman, E A; Simonsen, V; Ferreira, P; Telles, M A; Riley, L W

2017-08-01

A cohort of household contacts of tuberculosis (TB) index cases from four public health clinics in São Paulo, Brazil. To measure the association between diabetes mellitus (DM) among household contacts and recent-transmission TB (RT TB). Index TB cases (n = 263) identified from 2001 to 2002 in São Paulo, whose household contacts (n = 1383) were monitored for active TB until December 2010. From 2001 to 2010, there were 29 cases of RT TB among household contacts (cumulative incidence 2.1%, 95%CI 1.4-2.9). DM in household contacts was associated with RT TB (OR 3.96, 95%CI 1.33-11.79) even after adjustment for human immunodeficiency virus (HIV) status, smoking and alcohol use (adjusted OR [aOR] 3.21, 95%CI 1.01-10.19). HIV infection was also associated with RT TB (OR 6.40, 95%CI 1.40-29.40; aOR 4.81, 95%CI 0.96-24.18). Household contact DM was not associated with non-RT TB (OR 1.27, 95%CI 0.30-5.40). The time to diagnosis of TB was shorter in household contacts with and without DM (P = 0.035) and in household contacts with and without HIV (P = 0.0002). Household contact DM was associated with an increased risk of RT TB in a cohort in Brazil, lending support to the active screening of household contacts with DM for TB in Brazil.

Market assessment of tuberculosis diagnostics in Brazil in 2012.

PubMed

2014-01-01

Improved diagnostics for the diagnosis of tuberculosis (TB) are urgently needed. However, test developers and investors require market size data to support new product development. This study assessed the served available market for TB diagnostics in Brazil in 2012 and the market segmentation in the public and private sectors. Data were collected on test volumes done in the public and private sectors for the diagnosis of latent and active TB, drug susceptibility testing and treatment follow-up. Tests included were tuberculin skin tests, interferon-gamma releases assays, smear microscopy, solid and liquid cultures, nucleic acid amplification tests and phenotypic drug susceptibility tests. The data were collected by means of an electronic survey via the Brazilian State laboratories and from sales information provided by manufacturers. Test costs for the public sector were calculated using a components approach, while costs for the private sector were based on prices paid by patients. The overall market value (expenditure) for the entire country was calculated using the public sector test costs. During 2012, an estimated total of 2.4 million TB diagnostic tests were done in Brazil, resulting in an estimated overall market value of USD 17.2 million. The public sector accounted for 91% of the test volumes and 88% of the market value. Smear microscopy was the most commonly test (n = 1.3 million; 55% of total) at an estimated value of USD 3.7 million. Culture overall (n = 302,761) represented 13% of test volumes and 40% (USD 6.9 million) of the market value. On average, USD 208 was spent on TB diagnostics for every notified TB patient in Brazil, in 2012. The TB diagnostics market value in Brazil in 2012 was over USD 17 million. These study results will help test developers to understand the current and potential market for replacement or add-on diagnostic technologies.

Market Assessment of Tuberculosis Diagnostics in Brazil in 2012

PubMed Central

2014-01-01

Background Improved diagnostics for the diagnosis of tuberculosis (TB) are urgently needed. However, test developers and investors require market size data to support new product development. This study assessed the served available market for TB diagnostics in Brazil in 2012 and the market segmentation in the public and private sectors. Methods Data were collected on test volumes done in the public and private sectors for the diagnosis of latent and active TB, drug susceptibility testing and treatment follow-up. Tests included were tuberculin skin tests, interferon-gamma releases assays, smear microscopy, solid and liquid cultures, nucleic acid amplification tests and phenotypic drug susceptibility tests. The data were collected by means of an electronic survey via the Brazilian State laboratories and from sales information provided by manufacturers. Test costs for the public sector were calculated using a components approach, while costs for the private sector were based on prices paid by patients. The overall market value (expenditure) for the entire country was calculated using the public sector test costs. Results During 2012, an estimated total of 2.4 million TB diagnostic tests were done in Brazil, resulting in an estimated overall market value of USD 17.2 million. The public sector accounted for 91% of the test volumes and 88% of the market value. Smear microscopy was the most commonly test (n = 1.3 million; 55% of total) at an estimated value of USD 3.7 million. Culture overall (n = 302,761) represented 13% of test volumes and 40% (USD 6.9 million) of the market value. On average, USD 208 was spent on TB diagnostics for every notified TB patient in Brazil, in 2012. Conclusion The TB diagnostics market value in Brazil in 2012 was over USD 17 million. These study results will help test developers to understand the current and potential market for replacement or add-on diagnostic technologies. PMID:25099237

Successful TB treatment induces B-cells expressing FASL and IL5RA mRNA.

PubMed

van Rensburg, Ilana C; Wagman, Chandre; Stanley, Kim; Beltran, Caroline; Ronacher, Katharina; Walzl, Gerhard; Loxton, Andre G

2017-01-10

Activated B-cells increase T-cell behaviour during autoimmune disease and other infections by means of cytokine production and antigen-presentation. Functional studies in experimental autoimmune encephalomyelitis (EAE) indicate that B-cell deficiencies, and a lack of IL10 and IL35 leads to a poor prognosis. We hypothesised that B-cells play a role during tuberculosis. We evaluated B-cell mRNA expression using real-time PCR from healthy community controls, individuals with other lung diseases and newly diagnosed untreated pulmonary TB patients at three different time points (diagnosis, month 2 and 6 of treatment).We show that FASLG, IL5RA, CD38 and IL4 expression was lower in B-cells from TB cases compared to healthy controls. The changes in expression levels of CD38 may be due to a reduced activation of B-cells from TB cases at diagnosis. By month 2 of treatment, there was a significant increase in the expression of APRIL and IL5RA in TB cases. Furthermore, after 6 months of treatment, APRIL, FASLG, IL5RA and CD19 were upregulated in B-cells from TB cases. The increase in the expression of APRIL and CD19 suggests that there may be restored activation of B-cells following anti-TB treatment. The upregulation of FASLG and IL5RA indicates that B-cells expressing regulatory genes may play an important role in the protective immunity against M.tb infection. Our results show that increased activation of B-cells is present following successful TB treatment, and that the expression of FASLG and IL5RA could potentially be utilised as a signature to monitor treatment response.

Fluorometric determination of the activity of alkaline phosphatase based on the competitive binding of gold nanoparticles and pyrophosphate to CePO4:Tb nanorods.

PubMed

Xu, Ai-Zhen; Zhang, Li; Zeng, Hui-Hui; Liang, Ru-Ping; Qiu, Jian-Ding

2018-05-09

A fluorometric method is described for the determination of the activity of alkaline phosphatase (ALP). It relies on the competition between gold nanoparticles (AuNPs) and pyrophosphate (PPi) for the coordination sites on the surface of CePO 4 :Tb nanorods. The green fluorescence of the CePO 4 :Tb is reduced in the presence of AuNPs due to fluorescence resonance energy transfer (FRET), but can be restored on addition of PPi due to the stronger affinity of PPi to the CePO 4 :Tb. In the presence of ALP, PPi is hydrolyzed to form phosphate which has much weaker affinity for the CePO 4 :Tb. Hence, the AuNPs will reassemble on the CePO 4 :Tb, and fluorescence is reduced. Fluorescence drops linearly in the 0.2 to 100 U·L -1 activity range, and the detection limit is 60 mU·L -1 (at S/N = 3). The method does not require any modification of the surface of the CePO 4 :Tb and is highly sensitive and selective. The inhibition of ALP activity by Na 3 VO 4 was also studied. In our perception, the method may find application in the diagnosis of ALP-related diseases, in screening for inhibitors, and in studies on ALP-related functions in biological systems. Graphical abstract A assay for the detection of alkaline phosphatase is proposed based on the fluorescence resonance energy transfer between CePO 4 :Tb and AuNPs. It relies on the competitive binding of AuNPs and pyrophosphate (PPi) to CePO 4 :Tb and the hydrolysis of PPi by ALP.

Tuberculosis Outbreak in a Primary School, Milan, Italy

PubMed Central

Faccini, Marino; Codecasa, Luigi Ruffo; Ciconali, Giorgio; Cammarata, Serafina; Borriello, Catia Rosanna; De Gioia, Costanza; Za, Alessandro; Marino, Andrea Filippo; Ferrarese, Maurizio; Gesu, Giovanni; Mazzola, Ester; Castaldi, Silvana

2013-01-01

Investigation of an outbreak of tuberculosis (TB) in a primary school in Milan, Italy, found 15 schoolchildren had active TB disease and 173 had latent TB infection. TB was also identified in 2 homeless men near the school. Diagnostic delay, particularly in the index case-patient, contributed to the transmission of infection. PMID:23621942

Common patterns and disease-related signatures in tuberculosis and sarcoidosis.

PubMed

Maertzdorf, Jeroen; Weiner, January; Mollenkopf, Hans-Joachim; Bauer, Torsten; Prasse, Antje; Müller-Quernheim, Joachim; Kaufmann, Stefan H E

2012-05-15

In light of the marked global health impact of tuberculosis (TB), strong focus has been on identifying biosignatures. Gene expression profiles in blood cells identified so far are indicative of a persistent activation of the immune system and chronic inflammatory pathology in active TB. Definition of a biosignature with unique specificity for TB demands that identified profiles can differentiate diseases with similar pathology, like sarcoidosis (SARC). Here, we present a detailed comparison between pulmonary TB and SARC, including whole-blood gene expression profiling, microRNA expression, and multiplex serum analytes. Our analysis reveals that previously disclosed gene expression signatures in TB show highly similar patterns in SARC, with a common up-regulation of proinflammatory pathways and IFN signaling and close similarity to TB-related signatures. microRNA expression also presented a highly similar pattern in both diseases, whereas cytokines in the serum of TB patients revealed a slightly elevated proinflammatory pattern compared with SARC and controls. Our results indicate several differences in expression between the two diseases, with increased metabolic activity and significantly higher antimicrobial defense responses in TB. However, matrix metallopeptidase 14 was identified as the most distinctive marker of SARC. Described communalities as well as unique signatures in blood profiles of two distinct inflammatory pulmonary diseases not only have considerable implications for the design of TB biosignatures and future diagnosis, but they also provide insights into biological processes underlying chronic inflammatory disease entities of different etiology.

Drug resistance mechanisms and novel drug targets for tuberculosis therapy.

PubMed

Islam, Md Mahmudul; Hameed, H M Adnan; Mugweru, Julius; Chhotaray, Chiranjibi; Wang, Changwei; Tan, Yaoju; Liu, Jianxiong; Li, Xinjie; Tan, Shouyong; Ojima, Iwao; Yew, Wing Wai; Nuermberger, Eric; Lamichhane, Gyanu; Zhang, Tianyu

2017-01-20

Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance. Copyright © 2016 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

Predictors of hospitalization of tuberculosis patients in Montreal, Canada: a retrospective cohort study.

PubMed

Ronald, Lisa A; FitzGerald, J Mark; Benedetti, Andrea; Boivin, Jean-François; Schwartzman, Kevin; Bartlett-Esquilant, Gillian; Menzies, Dick

2016-11-15

Hospitalization is the most costly health system component of tuberculosis (TB) control programs. Our objectives were to identify how frequently patients are hospitalized, and the factors associated with hospitalizations and length-of-stay (LOS) of TB patients in a large Canadian city. We extracted data from the Montreal TB Resource database, a retrospective cohort of all active TB cases reported to the Montreal Public Health Department between January 1996 and May 2007. Data included patient demographics, clinical characteristics, and dates of treatment and hospitalization. Predictors of hospitalization and LOS were estimated using logistic regression and Cox proportional hazards regression, respectively. There were 1852 active TB patients. Of these, 51% were hospitalized initially during the period of diagnosis and/or treatment initiation (median LOS 17.5 days), and 9.0% hospitalized later during treatment (median LOS 13 days). In adjusted models, patients were more likely to be hospitalized initially if they were children, had co-morbidities, smear-positive symptomatic pulmonary TB, cavitary or miliary TB, and multi- or poly-TB drug resistance. Factors predictive of longer initial LOS included having HIV, renal disease, symptomatic pulmonary smear-positive TB, multi- or poly-TB drug resistance, and being in a teaching hospital. We found a high hospitalization rate during diagnosis and treatment of patients with TB. Diagnostic delay due to low index of suspicion may result in patients presenting with more severe disease at the time of diagnosis. Earlier identification and treatment, through interventions to increase TB awareness and more targeted prevention programs, might reduce costly TB-related hospital use.

Achievements and challenges of the World Bank Loan/Department for International Development grant-assisted Tuberculosis Control Project in China.

PubMed

Kong, Peng; Jiang, Xu; Zhang, Ben; Jiang, Shi-wen; Liu, Bo

2011-07-01

In March 2002, the government of China launched the World Bank Loan/ Department for International Development-supported Tuberculosis (TB) Control Project to reduce the prevalence and mortality of TB. The project generated promising results in policy development, strengthening of TB control systems, patient treatment success, funds management, and the introduction of legislation. In light of the global TB epidemic and control environment, it is useful to review the TB control priorities of the project, summarize the achievements and experiences around its implementation.

Active case-finding for tuberculosis by mobile teams in Myanmar: yield and treatment outcomes.

PubMed

Myint, Ohnmar; Saw, Saw; Isaakidis, Petros; Khogali, Mohammed; Reid, Anthony; Hoa, Nguyen Binh; Kyaw, Thi Thi; Zaw, Ko Ko; Khaing, Tin Mi Mi; Aung, Si Thu

2017-06-02

Since 2005, the Myanmar National Tuberculosis Programme (NTP) has been implementing active case finding (ACF) activities involving mobile teams in hard-to-reach areas. This study revealed the contribution of mobile team activities to total tuberculosis (TB) case detection, characteristics of TB patients detected by mobile teams and their treatment outcomes. This was a descriptive study using routine programme data between October 2014 and December 2014. Mobile team activities were a one-stop service and included portable digital chest radiography (CXR) and microscopy of two sputum samples. The algorithm of the case detection included screening patients by symptoms, then by CXR followed by sputum microscopy for confirmation. Diagnosed patients were started on treatment and followed until a final outcome was ascertained. A total of 9 349 people with symptoms suggestive of TB were screened by CXR, with an uptake of 96.6%. Of those who were meant to undergo sputum smear microscopy, 51.4% had sputum examinations. Finally, 504 TB patients were identified by the mobile teams and the overall contribution to total TB case detection in the respective townships was 25.3%. Among total cases examined by microscopy, 6.4% were sputum smear positive TB. Treatment success rate was high as 91.8% in study townships compared to national rate 85% (2014 cohort). This study confirmed the feasibility and acceptability of ACF by mobile teams in hard-to-reach contexts, especially when equipped with portable, digital CXR machines that provided immediate results. However, the follow-up process of sputum examination created a significant barrier to confirmation of the diagnosis. In order to optimize the ACF through mobile team activity, future ACF activities were needed to be strengthened one stop service including molecular diagnostics or provision of sputum cups to all presumptive TB cases prior to CXR and testing if CXR suggestive of TB.

Progress and challenges in TB vaccine development

PubMed Central

Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H.E.; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

2018-01-01

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development. PMID:29568497

Progress and challenges in TB vaccine development.

PubMed

Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H E; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

2018-01-01

The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our "failed" trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

Synthesis, photoluminescence and biological properties of terbium(III) complexes with hydroxyketone and nitrogen containing heterocyclic ligands

NASA Astrophysics Data System (ADS)

Poonam; Kumar, Rajesh; Boora, Priti; Khatkar, Anurag; Khatkar, S. P.; Taxak, V. B.

2016-01-01

The ternary terbium(III) complexes [Tb(HDAP)3ṡbiq], [Tb(HDAP)3ṡdmph] and [Tb(HDAP)3ṡbathophen] were prepared by using methoxy substituted hydroxyketone ligand HDAP (2-hydroxy-4,6-dimethoxyacetophenone) and an ancillary ligand 2,2-biquinoline or 5,6-dimethyl-1,10-phenanthroline or bathophenanthroline respectively. The ligand and synthesized complexes were characterised based on elemental analysis, FT-IR and 1H NMR. Thermal behaviour of the synthesized complexes illustrates the general decomposition patterns of the complexes by thermogravimetric analysis. Photophysical properties such as excitation spectra, emission spectra and luminescence decay curves of the complexes were investigated in detail. The main green emitting peak at 548 nm can be attributed to 5D4 → 7F5 of Tb3+ ion. Thus, these complexes might be used to make a bright green light-emitting diode for display purpose. In addition the in vitro antibacterial activities of HDAP and its Tb(III) complexes against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and antifungal activities against Candida albicans and Aspergillus niger are reported. The Tb3+ complexes were found to be more potent antimicrobial agent as compared to the ligand. Among all these complexes, [Tb(HDAP)3ṡbathophen] exhibited excellent antimicrobial activity which proves its potential usefulness as an antimicrobial agent. Furthermore, in vitro antioxidant activity tests were carried out by using DPPH method which indicates that the complexes have considerable antioxidant activity when compared with the standard ascorbic acid.

[CLINICAL UTILITY OF T-SPOT.TB ASSAY WITH T-Cell Xtend REAGENT FOR ACTIVE TUBERCULOSIS DIAGNOSIS IN THE FIELD TEST AT OUR HOSPITAL].

PubMed

Nemoto, Kenji; Oh-ishi, Shuji; Taguchi, Masato; Hyodo, Kentaro; Kanazawa, Jun; Miura, Yukiko; Takaku, Takio; Usui, Shingo; Hayashihara, Kenji; Saito, Takefumi

2016-04-01

T-SPOT.TB (T-SPOT), an interferon-gamma release assay, has shown promise as a diagnostic tool for active tuberculosis (TB), and its use is expanding. Addition of the T-Cell Xtend (TCX) reagent may allow delayed processing, and this characteristic is important for using this test in the field. However, limited data is available on the usefulness of T-SPOT with TCX as a field test for diagnosing active TB. To investigate the clinical utility of T-SPOT with TCX and the risk factors for a false-negative result in patients with active TB. A total of 57 patients with active TB who underwent the T-SPOT test with TCX prior to treatment were enrolled between May 2013 and May 2015. One patient with an indeterminate result for T-SPOT was excluded; therefore, the data of 56 patients were eventually included in the final analysis. The basic characteristics and clinical findings were compared between the true-positive and false-negative T-SPOT groups. Of the 56 patients, 40 (71.4%), 13 (23.2%), 3 (5.4%) had true-positive, false-negative, and borderline T-SPOT results, respectively. This study did not reveal any significant risk factors for a false-negative T-SPOT result. In this clinical study, the proportion of patients with a false-negative result for T-SPOT with TCX for active TB was higher than that reported previously. Therefore, careful interpretation of a negative result for T-SPOT with TCX is necessary, regardless of the patient's background.

Risk factors for latent tuberculosis infection in close contacts of active tuberculosis patients in South Korea: a prospective cohort study.

PubMed

Lee, Seung Jun; Lee, Seung Hun; Kim, You Eun; Cho, Yu Ji; Jeong, Yi Yeong; Kim, Ho Cheol; Lee, Jong Deog; Kim, Jang Rak; Hwang, Young Sil; Kim, Hee Jin; Menzies, Dick

2014-11-18

The diagnosis and treatment of latent tuberculosis infection (LTBI) have become mandatory to reduce the burden of tuberculosis worldwide. Close contacts of active TB patients are at high risk of both active and LTBI. The aim of this study is to identify the predominant risk factors of contracting LTBI, persons in close contact with TB patients were recruited. This study also aimed to compare the efficacy of the tuberculin skin test (TST) and QuantiFERON(®)-TB GOLD (QFT-G) to diagnose LTBI. Close contacts of active pulmonary TB patients visiting a hospital in South Korea were diagnosed for LTBI using TST and/or QFT-G. The association of positive TST and/or QFT-G with the following factors was estimated: age, gender, history of Bacillius Calmette-Guerin (BCG) vaccination, history of pulmonary TB, cohabitation status, the acid-fast bacilli smear status, and presence of cough in source cases. Of 308 subjects, 38.0% (116/305) were TST positive and 28.6% (59/206) were QFT-G positive. TST positivity was significantly associated with male gender (OR: 1.734; 95% CI: 1.001-3.003, p =0.049), history of pulmonary TB (OR: 4.130; 95% CI: 1.441-11.835, p =0.008) and household contact (OR: 2.130; 95% CI: 1.198-3.786, p =0.01) after adjustment for confounding variables. The degree of concordance between TST and QFT-G was fair (70.4%, κ =0.392). A prevalence of LTBI among close contacts of active pulmonary TB patients was high, and prior TB history and being a household contact were risk factors of LTBI in the study population.

Falling Short of the Rights to Health and Scientific Progress

PubMed Central

Henry, Ian; Lessem, Erica

2016-01-01

Abstract The incorporation of human rights-based approaches into TB programs is gaining traction, but little work has explored the application of human rights norms and principles to TB research (a domain traditionally left to bioethics). TB research is gravely underfunded, and the scarcity of resources for TB drug development has contributed to the stubborn persistence of the TB epidemic and helped to create the conditions under which drug-resistant TB has developed and spread. This article shows how human rights—particularly human rights standards, norms, and principles related to the rights to health and benefits of scientific progress—can provide insight into understanding how underfunding TB drug research undermines efforts to secure access to safe, effective, and optimized treatment for all people with TB. By analyzing TB research in relation to the rights to health and scientific progress, we aim to clarify the legal obligations of governments to improve the TB drug research system, fund TB research, and make medical advances that result from research available to all people with TB. PMID:27780996

Smartphone Applications to Support Tuberculosis Prevention and Treatment: Review and Evaluation.

PubMed

Iribarren, Sarah J; Schnall, Rebecca; Stone, Patricia W; Carballo-Diéguez, Alex

2016-05-13

Tuberculosis (TB) remains a major global health problem and is the leading killer due to a single infectious disease. Mobile health (mHealth)-based tools such as smartphone apps have been suggested as tools to support TB control efforts (eg, identification, contact tracing, case management including patient support). The purpose of this review was to identify and assess the functionalities of mobile apps focused on prevention and treatment of TB. We searched 3 online mobile app stores. Apps were included if they were focused on TB and were in English, Spanish, or Portuguese. For each included app, 11 functionalities were assessed (eg, inform, instruct, record), and searches were conducted to identify peer-review publications of rigorous testing of the available apps. A total of 1332 potentially relevant apps were identified, with 24 meeting our inclusion criteria. All of the apps were free to download, but 7 required login and password and were developed for specific clinics, regional sites, or research studies. Targeted users were mainly clinicians (n=17); few (n=4) apps were patient focused. Most apps (n=17) had 4 or fewer functions out of 11 (range 1-6). The most common functionalities were inform and record (n=15). Although a number of apps were identified with various functionalities to support TB efforts, some had issues such as incorrect spelling and grammar, inconsistent responses to data entry, problems with crashing, or links to features that had no data. Of more concern, some apps provided potentially harmful information to patients, such as links to natural remedies for TB and natural healers. One-third of the apps (8/24) had not been updated for more than a year and may no longer be supported. Peer-reviewed publications were identified for only two of the included apps. In the gray literature (not found in the app stores), three TB-related apps were identified as in progress, being launched, or tested. Apps identified for TB prevention and treatment had minimal functionality, primarily targeted frontline health care workers, and focused on TB information (eg, general information, guidelines, and news) or data collection (eg, replace paper-based notification or tracking). Few apps were developed for use by patients and none were developed to support TB patient involvement and management in their care (eg, follow-up alerts/reminders, side effects monitoring) or improve interaction with their health care providers, limiting the potential of these apps to facilitate patient-centered care. Our evaluation shows that more refined work is needed to be done in the area of apps to support patients with active TB. Involving TB patients in treatment in the design of these apps is recommended.

Tuberculosis screening among persons with diabetes mellitus in Pune, India.

PubMed

Mave, Vidya; Nimkar, Smita; Prasad, Haridas; Kadam, Dileep; Meshram, Sushant; Lokhande, Rahul; Gupte, Nikhil; Jain, Divyashri; Gupta, Amita; Golub, Jonathan E

2017-06-02

Diabetes mellitus (DM) increases tuberculosis (TB) risk, and there is increasing concern over the public health implications of the convergence of these two epidemics. Screening for TB among people with DM is now recommended in India. People with DM seeking care at a large public sector tertiary care hospital clinic in Pune, India, were screened for TB from June 2015 to May 2016. All consenting people with DM were screened for TB at each clinic visit using a five-item, WHO-recommended questionnaire and those with TB symptoms and/or risk factors were tested for active TB using sputum smear microscopty, Xpert® MTB/RIF and TB culture. Categorical data and continuous variables were summarized using descriptive statistics. The x 2 test or Wilcoxon rank-sum test was used to ascertain significant associations between categorical and continuous variables, respectively. Among 630 adults approached for screening, median age was 60 (interquartile range (IQR), 57-64) years and 350 (56%) were females. Median hemoglobin A1c (HbA1c) was 8.7% (IQR, 6.7-9.9) and 444 (70.5%) were poorly controlled DM (HbA1c > 7). Forty-four (7%) had prior history of TB but the proportion with TB risk factors at screening was low (<5%). While 18% of participants reported any TB symptoms, none of these patients were diagnosed with culture confirmed TB. Our study failed to yield any active TB cases using a WHO-recommended questionnaire among people with DM. High TB risk populations among people with DM must be identified if TB screening is to be feasible in settings such as India where the DM epidemic continues to rise.

Tuberculosis among older adults in Zambia: burden and characteristics among a neglected group.

PubMed

Coffman, Jenna; Chanda-Kapata, Pascalina; Marais, Ben J; Kapata, Nathan; Zumla, Alimuddin; Negin, Joel

2017-10-12

The 2010 Global Burden of Disease estimates show that 57% of all TB deaths globally occurred among adults older than 50 years of age. Few studies document the TB burden among older adults in Southern Africa. We focused on adults older than 55 years to assess the relative TB burden and associated demographic factors. A cross sectional nationally representative TB prevalence survey conducted of Zambian residents aged 15 years and above from 66 clusters across all the 10 provinces of Zambia. Evaluation included testing for TB as well as an in-depth questionnaire. We compared survey data for those aged 55 and older to those aged 15-54 years. Survey results were also compared with 2013 routinely collected programmatic notification data to generate future hypotheses regarding active and passive case finding. Among older adults with TB, 30/ 54 (55.6%) were male, 3/27 (11.1%) were HIV infected and 35/54 (64.8%) lived in rural areas. TB prevalence was higher in those aged ≥55 (0.7%) than in the 15-54 age group (0.5%). Males had higher rates of TB across both age groups with 0.7% (15-54) and 1.0% (≥55) compared with females 0.4% (15-54) and 0.6% (≥55). In rural areas, the prevalence of TB was significantly higher among older than younger adults (0.7% vs 0.3%), while the HIV infection rate was among TB patients was lower (11.1% vs 30.8%). The prevalence survey detected TB in 54/7484 (0.7%) of older adults compared to 3619/723,000 (0.5%) reported in 2013 programmatic data. High TB rates among older adults in TB endemic areas justify consideration of active TB case finding and prevention strategies.

The Tuberculosis Cascade of Care in India’s Public Sector: A Systematic Review and Meta-analysis

PubMed Central

Satyanarayana, Srinath; Pai, Madhukar; Thomas, Beena E.; Chadha, Vineet K.; Swaminathan, Soumya; Mayer, Kenneth H.

2016-01-01

Background India has 23% of the global burden of active tuberculosis (TB) patients and 27% of the world’s “missing” patients, which includes those who may not have received effective TB care and could potentially spread TB to others. The “cascade of care” is a useful model for visualizing deficiencies in case detection and retention in care, in order to prioritize interventions. Methods and Findings The care cascade constructed in this paper focuses on the Revised National TB Control Programme (RNTCP), which treats about half of India’s TB patients. We define the TB cascade as including the following patient populations: total prevalent active TB patients in India, TB patients who reach and undergo evaluation at RNTCP diagnostic facilities, patients successfully diagnosed with TB, patients who start treatment, patients retained to treatment completion, and patients who achieve 1-y recurrence-free survival. We estimate each step of the cascade for 2013 using data from two World Health Organization (WHO) reports (2014–2015), one WHO dataset (2015), and three RNTCP reports (2014–2016). In addition, we conduct three targeted systematic reviews of the scientific literature to identify 39 unique articles published from 2000–2015 that provide additional data on five indicators that help estimate different steps of the TB cascade. We construct separate care cascades for the overall population of patients with active TB and for patients with specific forms of TB—including new smear-positive, new smear-negative, retreatment smear-positive, and multidrug-resistant (MDR) TB. The WHO estimated that there were 2,700,000 (95%CI: 1,800,000–3,800,000) prevalent TB patients in India in 2013. Of these patients, we estimate that 1,938,027 (72%) TB patients were evaluated at RNTCP facilities; 1,629,906 (60%) were successfully diagnosed; 1,417,838 (53%) got registered for treatment; 1,221,764 (45%) completed treatment; and 1,049,237 (95%CI: 1,008,775–1,083,243), or 39%, of 2,700,000 TB patients achieved the optimal outcome of 1-y recurrence-free survival. The separate cascades for different forms of TB highlight different patterns of patient attrition. Pretreatment loss to follow-up of diagnosed patients and post-treatment TB recurrence were major points of attrition in the new smear-positive TB cascade. In the new smear-negative and MDR TB cascades, a substantial proportion of patients who were evaluated at RNTCP diagnostic facilities were not successfully diagnosed. Retreatment smear-positive and MDR TB patients had poorer treatment outcomes than the general TB population. Limitations of our analysis include the lack of available data on the cascade of care in the private sector and substantial uncertainty regarding the 1-y period prevalence of TB in India. Conclusions Increasing case detection is critical to improving outcomes in India’s TB cascade of care, especially for smear-negative and MDR TB patients. For new smear-positive patients, pretreatment loss to follow-up and post-treatment TB recurrence are considerable points of attrition that may contribute to ongoing TB transmission. Future multisite studies providing more accurate information on key steps in the public sector TB cascade and extension of this analysis to private sector patients may help to better target interventions and resources for TB control in India. PMID:27780217

Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection

PubMed Central

Scordo, Julia M.; Arcos, Jesús; Kelley, Holden V.; Diangelo, Lauren; Sasindran, Smitha J.; Youngmin, Ellie; Wewers, Mark D.; Wang, Shu-Hua; Balada-Llasat, Joan-Miquel; Torrelles, Jordi B.

2017-01-01

In 2016, the World Health Organization reported that one person dies of tuberculosis (TB) every 21 s. A host environment that Mycobacterium tuberculosis (M.tb) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. We published that human lung mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e., interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release, and does not induce cytotoxicity. Unexpectedly, these ALF fragment-derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site. PMID:28373877

Mycobacterium tuberculosis Cell Wall Fragments Released upon Bacterial Contact with the Human Lung Mucosa Alter the Neutrophil Response to Infection.

PubMed

Scordo, Julia M; Arcos, Jesús; Kelley, Holden V; Diangelo, Lauren; Sasindran, Smitha J; Youngmin, Ellie; Wewers, Mark D; Wang, Shu-Hua; Balada-Llasat, Joan-Miquel; Torrelles, Jordi B

2017-01-01

In 2016, the World Health Organization reported that one person dies of tuberculosis (TB) every 21 s. A host environment that Mycobacterium tuberculosis ( M.tb ) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. We published that human lung mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e., interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release, and does not induce cytotoxicity. Unexpectedly, these ALF fragment-derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site.

Granulysin-Expressing CD4+ T Cells as Candidate Immune Marker for Tuberculosis during Childhood and Adolescence

PubMed Central

Mueller, Henrik; Faé, Kellen C.; Magdorf, Klaus; Ganoza, Christian A.; Wahn, Ulrich; Guhlich, Ute; Feiterna-Sperling, Cornelia; Kaufmann, Stefan H. E.

2011-01-01

Background Granulysin produced by cytolytic T cells directly contributes to immune defense against tuberculosis (TB). We investigated granulysin as a candidate immune marker for childhood and adolescent TB. Methods Peripheral blood mononuclear cells (PBMC) from children and adolescents (1–17 years) with active TB, latent TB infection (LTBI), nontuberculous mycobacteria (NTM) infection and from uninfected controls were isolated and restimulated in a 7-day restimulation assay. Intracellular staining was then performed to analyze antigen-specific induction of activation markers and cytotoxic proteins, notably, granulysin in CD4+ CD45RO+ memory T cells. Results CD4+ CD45RO+ T cells co-expressing granulysin with specificity for Mycobacterium tuberculosis (Mtb) were present in high frequency in TB-experienced children and adolescents. Proliferating memory T cells (CFSElowCD4+CD45RO+) were identified as main source of granulysin and these cells expressed both central and effector memory phenotype. PBMC from study participants after TB drug therapy revealed that granulysin-expressing CD4+ T cells are long-lived, and express several activation and cytotoxicity markers with a proportion of cells being interferon-gamma-positive. In addition, granulysin-expressing T cell lines showed cytolytic activity against Mtb-infected target cells. Conclusions Our data suggest granulysin expression by CD4+ memory T cells as candidate immune marker for TB infection, notably, in childhood and adolescence. PMID:22216262

Technology and tuberculosis control: the OUT-TB Web experience.

PubMed

Guthrie, Jennifer L; Alexander, David C; Marchand-Austin, Alex; Lam, Karen; Whelan, Michael; Lee, Brenda; Furness, Colin; Rea, Elizabeth; Stuart, Rebecca; Lechner, Julia; Varia, Monali; McLean, Jennifer; Jamieson, Frances B

2017-04-01

Develop a tool to disseminate integrated laboratory, clinical, and demographic case data necessary for improved contact tracing and outbreak detection of tuberculosis (TB). In 2007, the Public Health Ontario Laboratories implemented a universal genotyping program to monitor the spread of TB strains within Ontario. Ontario Universal Typing of TB (OUT-TB) Web utilizes geographic information system (GIS) technology with a relational database platform, allowing TB control staff to visualize genotyping matches and microbiological data within the context of relevant epidemiological and demographic data. OUT-TB Web is currently available to the 8 health units responsible for >85% of Ontario's TB cases and is a valuable tool for TB case investigation. Users identified key features to implement for application enhancements, including an e-mail alert function, customizable heat maps for visualizing TB and drug-resistant cases, socioeconomic map layers, a dashboard providing TB surveillance metrics, and a feature for animating the geographic spread of strains over time. OUT-TB Web has proven to be an award-winning application and a useful tool. Developed and enhanced using regular user feedback, future versions will include additional data sources, enhanced map and line-list filter capabilities, and development of a mobile app. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Addressing diabetes mellitus as part of the strategy for ending TB

PubMed Central

Harries, Anthony D.; Kumar, Ajay M.V.; Satyanarayana, Srinath; Lin, Yan; Zachariah, Rony; Lönnroth, Knut; Kapur, Anil

2016-01-01

As we enter the new era of Sustainable Development Goals, the international community has committed to ending the TB epidemic by 2030 through implementation of an ambitious strategy to reduce TB-incidence and TB-related mortality and avoiding catastrophic costs for TB-affected families. Diabetes mellitus (DM) triples the risk of TB and increases the probability of adverse TB treatment outcomes such as failure, death and recurrent TB. The rapidly escalating global epidemic of DM means that DM needs to be addressed if TB-related milestones and targets are to be achieved. WHO and the International Union Against Tuberculosis and Lung Disease's Collaborative Framework for Care and Control of Tuberculosis and Diabetes, launched in 2011, provides a template to guide policy makers and implementers to combat the epidemics of both diseases. However, more evidence is required to answer important questions about bi-directional screening, optimal ways of delivering treatment, integration of DM and TB services, and infection control. This should in turn contribute to better and earlier TB case detection, and improved TB treatment outcomes and prevention. DM and TB collaborative care can also help guide the development of a more effective and integrated public health approach for managing non-communicable diseases. PMID:26884497

Dr Mario Raviglione, director of the Stop TB Department World Health Organization. Interview by Christo Hall.

PubMed

Raviglione, Mario

2012-03-01

Tuberculosis (TB) is a very global disease; there are over 9 million new incidences of TB every year with the vast majority of cases emerging in the developing world. As one of three major diseases associated with poverty it affects the areas where poverty is most prevalent, notably Asia and Africa. While the incidence rate has been slowly declining in the developed world it continues to pose a major health threat to even the most developed nations. To demonstrate the global, and persistent, nature of TB we asked Dr Mario Raviglione, Director of the World Health Organization's Stop TB Department to provide an analysis on the current TB situation in the United Kingdom and comment on what measures should be taken to alleviate the issue of TB in one of the world's richest countries.

Recent technological advancements in tuberculosis diagnostics - A review.

PubMed

Gupta, Shagun; Kakkar, Vipan

2018-09-15

Early diagnosis and on-time effective treatment are indispensable for Tuberculosis (TB) control - a life threatening infectious communicable disease. The conventional techniques for diagnosing TB normally take two to three weeks. This delay in diagnosis and further increase in detection complexity due to the emerging risks of XDR-TB (Extensively drug Resistant-TB) and MDR-TB (Multidrug Resistant-TB) are evoking interest of researchers in the field of developing rapid TB detection techniques such as biosensing and other point-of-care (POC) techniques. Biosensing technologies along with the collaboration with nanotechnology have enormous potential to boost the MTB detection and for overall management in clinical diagnosis. A diverse range of portable, sensitive and rapid biosensors based on different signal transducer principles and with different biomarkers detection capabilities have been developed for TB detection in the early stages. Further, a lot of progress has been achieved over the years in developing various point-of-care diagnostic tools including non-molecular methods and molecular techniques. The objective of this study is to present a succinct review of the available TB detection techniques that are either in use or under development. The focus of this review is on the current developments occurred in nano-biosensing technologies. A synopsis of ameliorations in different non-molecular diagnostic tools and progress in the field of molecular techniques along with the role of emerging Lab-on-Chip technology for diagnosing and mitigating the TB consequences have also been presented. Copyright © 2018 Elsevier B.V. All rights reserved.

Muscle volume is related to trabecular and cortical bone architecture in typically developing children

PubMed Central

Bajaj, Deepti; Allerton, Brianne M.; Kirby, Joshua T.; Miller, Freeman; Rowe, David A.; Pohlig, Ryan T.; Modlesky, Christopher M.

2016-01-01

Introduction Muscle is strongly related to cortical bone architecture in children; however, the relationship between muscle volume and trabecular bone architecture is poorly studied. The aim of this study was to determine if muscle volume is related to trabecular bone architecture in children and if the relationship is different than the relationship between muscle volume and cortical bone architecture. Materials and methods Forty typically developing children (20 boys and 20 girls; 6 to 12 y) were included in the study. Measures of trabecular bone architecture [apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th), and trabecular separation (appTb.Sp)] in the distal femur, cortical bone architecture [(cortical volume, medullary volume, total volume, polar moment of inertia (J) and section modulus (Z)] in the midfemur, muscle volume in the midthigh and femur length were assessed using magnetic resonance imaging. Total and moderate-to-vigorous physical activity were assessed using an accelerometer-based activity monitor worn around the waist for four days. Calcium intake was assessed using diet records. Relationships among the measures were tested using multiple linear regression analysis. Results Muscle volume was moderately-to-strongly related to measures of trabecular bone architecture [appBV/TV (r = 0.81, appTb.N (r = 0.53), appTb.Th (r = 0.67), appTb.Sp (r = −0.71; all p < 0.001] but more strongly related to measures of cortical bone architecture [cortical volume (r = 0.96), total volume (r = 0.94), Z (r = 0.94) and J (r = 0.92; all p < 0.001)]. Similar relationships were observed between femur length and measures of trabecular (p < 0.01) and cortical (p < 0.001) bone architecture. Sex, physical activity and calcium intake were not related to any measure of bone architecture (p > 0.05). Because muscle volume and femur length were strongly related (r = 0.91, p < 0.001), muscle volume was scaled for femur length (muscle volume/femur length2.77). When muscle volume/femur length2.77 was included in a regression model with femur length, sex, physical activity and calcium intake, muscle volume/femur length2.77 was a significant predictor of appBV/TV, appTb.Th and appTb.Sp (partial r = 0.44 to 049, p < 0.05) and all measures of cortical bone architecture (partial r = 0.47 to 054; p < 0.01). Conclusions The findings suggest that muscle volume in the midthigh is related to trabecular bone architecture in the distal femur of children. The relationship is weaker than the relationship between muscle volume in the midthigh and cortical bone architecture in the midfemur, but the discrepancy is driven, in large part, by the greater dependence of cortical bone architecture measures on femur length. PMID:26187197

Macronutrient intake and body composition changes during anti-tuberculosis therapy in adults

PubMed Central

Frediani, Jennifer K.; Sanikidze, Ekaterina; Kipiani, Maia; Tukvadze, Nestani; Hebbar, Gautam; Ramakrishnan, Usha; Jones, Dean P.; Easley, Kirk A.; Shenvi, Neeta; Kempker, Russell R.; Tangpricha, Vin; Blumberg, Henry M.; Ziegler, Thomas R.

2015-01-01

Background Malnutrition is common in patients with active tuberculosis (TB), yet little information is available on serial dietary intake or body composition in TB disease. Objective To evaluate macronutrient intake and body composition in individuals with newly diagnosed with TB over time. Design Adults with active pulmonary TB (n=191; 23 with multidrug resistant TB (MDR-TB) and 36 culture-negative household contacts (controls) enrolled in a clinical trial of high-dose cholecalciferol (vitamin D3) were studied. Macronutrient intake was determined at baseline, 8 and 16 weeks. Serial body composition was assessed by body mass index (BMI; kg/m2) and bioelectrical impedance analysis (BIA) to estimate fat mass and fat-free mass. Descriptive statistics, repeated measures ANOVA for changes over time and linear regression were used. Results At baseline, mean daily energy, protein, fat and carbohydrate (CHO) intakes were significantly higher, and body weight, BMI, fat-free mass and fat mass were significantly lower, between TB subjects and controls. These remained significant after adjusting for age, gender, employment status and smoking. In all TB subjects, baseline mean daily intakes of energy, fat and protein were adequate when compared to the US Dietary Reference Intakes and protein significantly increased over time (p<0.0001). Body weight, BMI, and fat and fat-free mass increased over time. MDR-TB patients exhibited lower body weight and fat-free mass over time, despite similar daily intake of kcal, protein, and fat. Conclusions Macronutrient intake was higher in TB patients than controls, but TB-induced wasting was evident. As macronutrient intake of TB subjects increased over time, there was a parallel increase in BMI, while body composition proportions were maintained. However, individuals with MDR-TB demonstrated concomitantly decreased body weight and fat-free mass over time versus drug-sensitive TB patients, despite increased macronutrient intake. Thus, MDR-TB appears to blunt anabolism to macronutrient intake, likely reflecting the catabolic effects of TB. PMID:25753551

Granulocytic Myeloid Derived Suppressor Cells Expansion during Active Pulmonary Tuberculosis Is Associated with High Nitric Oxide Plasma Level

PubMed Central

El Daker, Sary; Sacchi, Alessandra; Tempestilli, Massimo; Carducci, Claudia; Goletti, Delia; Vanini, Valentina; Colizzi, Vittorio; Lauria, Francesco Nicola; Martini, Federico; Martino, Angelo

2015-01-01

Tuberculosis (TB) is still the principal cause of death caused by a single infectious agent, and the balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. The aim of this work was to study the role of myeloid-derived suppressor cells (MDSCs) during active pulmonary tuberculosis at the site of infection. We observed an expansion of MDSCs in the lung and blood of patients with active TB, which are correlated with an enhanced amount of nitric oxide in the plasma. We also found that these cells have the remarkable ability to suppress T-cell response, suggesting an important role in the modulation of the immune response against TB. Interestingly, a trend in the diminution of MDSCs was found after an efficacious anti-TB therapy, suggesting that these cells may be used as a potential biomarker for monitoring anti-TB therapy efficacy. PMID:25879532

Design and optimization of a recombinant system for large-scale production of the MPT64 antigen from Mycobacterium tuberculosis.

PubMed

Geisbrecht, Brian V; Nikonenko, Boris; Samala, Rowena; Nakamura, Reiko; Nacy, Carol A; Sacksteder, Katherine A

2006-03-01

Early clinical trials of a potential new tuberculosis (TB) diagnostic, the Patch Test for Active TB (PTAT), used MPB64 protein that was purified from the spent medium of Bacillus Calmette-Guérin (BCG) Tokyo 172 vaccine production. The yield was poor, 0.05 mg/L, and the process for purification of the protein was complex, requiring four chromatographic steps. The combination of yield and purification complexity compromised the ability to produce the PTAT diagnostic in quantities sufficient for larger clinical trials and commercialization. We report here a highly efficient method for the overexpression and purification of recombinant MPT64 from Escherichia coli (rMPT64) based upon a mild insolubility of rMPT64 following induction, and scalable anion-exchange and gel filtration chromatographies. Yields of protein were improved substantially to approximately 250 mg/L, and resulted in a preparation greater than 98% pure. Quantitative release assays were developed and used with MALDI-TOF mass spectrometry to confirm the identity of rMPT64. Using a guinea pig model of active TB, we found that rMPT64 elicited a specific immune response indistinguishable from that of MPB64 purified from BCG Tokyo culture filtrates. These results describe the first efficient and scalable protocol for production of rMPT64, demonstrate its activity in an animal model of active TB, and lay the foundation of ongoing and future use of the PTAT in clinical settings.

Tuberculosis genotyping information management system: enhancing tuberculosis surveillance in the United States.

PubMed

Ghosh, Smita; Moonan, Patrick K; Cowan, Lauren; Grant, Juliana; Kammerer, Steve; Navin, Thomas R

2012-06-01

Molecular characterization of Mycobacterium tuberculosis complex isolates (genotyping) can be used by public health programs to more readily identify tuberculosis (TB) transmission. The Centers for Disease Control and Prevention's National Tuberculosis Genotyping Service has offered M. tuberculosis genotyping for every culture-confirmed case in the United States since 2004. The TB Genotyping Information Management System (TB GIMS), launched in March 2010, is a secure online database containing genotype results linked with case characteristics from the national TB registry for state and local TB programs to access, manage and analyze these data. As of September 2011, TB GIMS contains genotype results for 89% of all culture-positive TB cases for 2010. Over 400 users can generate local and national reports and maps using TB GIMS. Automated alerts on geospatially concentrated cases with matching genotypes that may represent outbreaks are also generated by TB GIMS. TB genotyping results are available to enhance national TB surveillance and apply genotyping results to conduct TB control activities in the United States. Published by Elsevier B.V.

Drug-resistant tuberculosis control in China: progress and challenges.

PubMed

Long, Qian; Qu, Yan; Lucas, Henry

2016-01-29

China has the second highest caseload of multidrug-resistant tuberculosis (MDR-TB) in the world. In 2009, the Chinese government agreed to draw up a plan for MDR-TB prevention and control in the context of a comprehensive health system reform launched in the same year. China is facing high prevalence rates of drug-resistant TB and MDR-TB. MDR-TB disproportionally affects the poor rural population and the highest rates are in less developed regions largely due to interrupted and/or inappropriate TB treatment. Most households with an affected member suffer a heavy financial burden because of a combination of treatment and other related costs. The influential Global Fund programme for MDR-TB control in China provides technical and financial support for MDR-TB diagnosis and treatment. However, this programme has a fixed timeline and cannot provide a long term solution. In 2009, the Bill and Melinda Gates Foundation, in cooperation with the National Health and Family Planning Commission of China, started to develop innovative approaches to TB/MDR-TB management and case-based payment mechanisms for treatment, alongside increased health insurance benefits for patients, in order to contain medical costs and reduce financial barriers to treatment. Although these efforts appear to be in the right direction, they may not be sufficient unless (a) domestic sources are mobilized to raise funding for TB/MDR-TB prevention and control and (b) appropriate incentives are given to both health facilities and their care providers. Along with the on-going Chinese health system reform, sustained government financing and social health protection schemes will be critical to ensure universal access to appropriate TB treatment in order to reduce risk of developing MDR-TB and systematic MDR-TB treatment and management.

Research Questions and Priorities for Tuberculosis: A Survey of Published Systematic Reviews and Meta-Analyses

PubMed Central

Nicolau, Ioana; Ling, Daphne; Tian, Lulu; Lienhardt, Christian; Pai, Madhukar

2012-01-01

Background Systematic reviews are increasingly informing policies in tuberculosis (TB) care and control. They may also be a source of questions for future research. As part of the process of developing the International Roadmap for TB Research, we did a systematic review of published systematic reviews on TB, to identify research priorities that are most frequently suggested in reviews. Methodology/Principal Findings We searched EMBASE, MEDLINE, Web of Science, and the Cochrane Library for systematic reviews and meta-analyses on any aspect of TB published between 2005 and 2010. One reviewer extracted data and a second reviewer independently extracted data from a random subset of included studies. In total, 137 systematic reviews, with 141 research questions, were included in this review. We used the UK Health Research Classification System (HRCS) to help us classify the research questions and priorities. The three most common research topics were in the area of detection, screening and diagnosis of TB (32.6%), development and evaluation of treatments and therapeutic interventions (23.4%), and TB aetiology and risk factors (19.9%). The research priorities determined were mainly focused on the discovery and evaluation of bacteriological TB tests and drug-resistant TB tests and immunological tests. Other important topics of future research were genetic susceptibility linked to TB and disease determinants attributed to HIV/TB. Evaluation of drug treatments for TB, drug-resistant TB and HIV/TB were also frequently proposed research topics. Conclusions Systematic reviews are a good source of key research priorities. Findings from our survey have informed the development of the International Roadmap for TB Research by the TB Research Movement. PMID:22848764

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery

PubMed Central

2017-01-01

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained. PMID:28983525

Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.

PubMed

Linciano, Pasquale; Dawson, Alice; Pöhner, Ina; Costa, David M; Sá, Monica S; Cordeiro-da-Silva, Anabela; Luciani, Rosaria; Gul, Sheraz; Witt, Gesa; Ellinger, Bernhard; Kuzikov, Maria; Gribbon, Philip; Reinshagen, Jeanette; Wolf, Markus; Behrens, Birte; Hannaert, Véronique; Michels, Paul A M; Nerini, Erika; Pozzi, Cecilia; di Pisa, Flavio; Landi, Giacomo; Santarem, Nuno; Ferrari, Stefania; Saxena, Puneet; Lazzari, Sandra; Cannazza, Giuseppe; Freitas-Junior, Lucio H; Moraes, Carolina B; Pascoalino, Bruno S; Alcântara, Laura M; Bertolacini, Claudia P; Fontana, Vanessa; Wittig, Ulrike; Müller, Wolfgang; Wade, Rebecca C; Hunter, William N; Mangani, Stefano; Costantino, Luca; Costi, Maria P

2017-09-30

Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei ( Tb ). We solved crystal structures of several Tb PTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of Tb PTR1 with low toxicity. In particular, compound 4m , a biphenyl-thiadiazole-2,5-diamine with IC 50 = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC 50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti- T. brucei agents can be obtained.

High Antigen Dose Is Detrimental to Post-Exposure Vaccine Protection against Tuberculosis

PubMed Central

Billeskov, Rolf; Lindenstrøm, Thomas; Woodworth, Joshua; Vilaplana, Cristina; Cardona, Pere-Joan; Cassidy, Joseph P.; Mortensen, Rasmus; Agger, Else Marie; Andersen, Peter

2018-01-01

Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), causes 1.8M deaths annually. The current vaccine, BCG, has failed to eradicate TB leaving 25% of the world’s population with latent Mtb infection (LTBI), and 5–10% of these people will reactivate and develop active TB. An efficient therapeutic vaccine targeting LTBI could have an enormous impact on global TB incidence, and could be an important aid in fighting multidrug resistance, which is increasing globally. Here we show in a mouse model using the H56 (Ag85B-ESAT-6-Rv2660) TB vaccine candidate that post-exposure, but not preventive, vaccine protection requires low vaccine antigen doses for optimal protection. Loss of protection from high dose post-exposure vaccination was not associated with a loss of overall vaccine response magnitude, but rather with greater differentiation and lower functional avidity of vaccine-specific CD4 T cells. High vaccine antigen dose also led to a decreased ability of vaccine-specific CD4 T cells to home into the Mtb-infected lung parenchyma, a recently discovered important feature of T cell protection in mice. These results underscore the importance of T cell quality rather than magnitude in TB-vaccine protection, and the significant role that antigen dosing plays in vaccine-mediated protection. PMID:29379507

High Antigen Dose Is Detrimental to Post-Exposure Vaccine Protection against Tuberculosis.

PubMed

Billeskov, Rolf; Lindenstrøm, Thomas; Woodworth, Joshua; Vilaplana, Cristina; Cardona, Pere-Joan; Cassidy, Joseph P; Mortensen, Rasmus; Agger, Else Marie; Andersen, Peter

2017-01-01

Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), causes 1.8M deaths annually. The current vaccine, BCG, has failed to eradicate TB leaving 25% of the world's population with latent Mtb infection (LTBI), and 5-10% of these people will reactivate and develop active TB. An efficient therapeutic vaccine targeting LTBI could have an enormous impact on global TB incidence, and could be an important aid in fighting multidrug resistance, which is increasing globally. Here we show in a mouse model using the H56 (Ag85B-ESAT-6-Rv2660) TB vaccine candidate that post-exposure, but not preventive, vaccine protection requires low vaccine antigen doses for optimal protection. Loss of protection from high dose post-exposure vaccination was not associated with a loss of overall vaccine response magnitude, but rather with greater differentiation and lower functional avidity of vaccine-specific CD4 T cells. High vaccine antigen dose also led to a decreased ability of vaccine-specific CD4 T cells to home into the Mtb-infected lung parenchyma, a recently discovered important feature of T cell protection in mice. These results underscore the importance of T cell quality rather than magnitude in TB-vaccine protection, and the significant role that antigen dosing plays in vaccine-mediated protection.

Lateral Flow Urine Lipoarabinomannan Assay (LF-LAM) for Diagnosis of Active Tuberculosis in HIV-Infected Adults: a Prospective Cohort Study

PubMed Central

Na Songkhla, Munjit; Tantipong, Hutsaya; Tongsai, Sasima; Angkasekwinai, Nasikarn

2017-01-01

Abstract Background Early diagnosis and treatment of active tuberculosis (TB) in HIV-positive patients is challenging. Tests based on the detection of mycobacterial lipoarabinomannan (LAM) antigen in urine have emerged as potential point-of-care tests for TB. However, limited data exists on their performance among HIV-TB co-infected patients from Southeast Asian countries. Methods We prospectively recruited HIV-positive adult patients with CD4 count less than or equal to 200/mm3 and symptoms suspected of active TB from two tertiary hospitals between December 2015 and March 2017. Freshly collected urine was applied to the Determine®-TB LAM Ag test strip (4 bands of graded intensity), using grade 1 cutoff. Diagnostic accuracy of urine LAM strip test were assessed against microbiological reference standard, defined as positive Mycobacterium tuberculosis cultured from one or more clinical specimens (definite TB) or composite reference standard including definite TB and probable TB, defined as those have symptoms consistent with TB and response to anti-TB treatment. Results A total of 280 patients were enrolled. Of whom, 72 (25.7%) and 65 (23.2%) had definite and probable TB. Amongst those with definite TB, LF-LAM test gave a sensitivity of 75.0% (95% CI 63.9–83.6), specificity of 86.0% (95% CI 79.4–90.8) and accuracy of 82.3% (95% CI 76.7–86.8). When compared with the composite reference standard, the test yielded a lower sensitivity (61.3%, 95% CI 53.0–69.1) and accuracy (73.9%, 95% CI 68.5–78.7), with equal specificity. The test showed the highest sensitivity (90.5%, 95% CI 77.9–96.2) and accuracy (85.9%, 95% CI 79.2–90.7) but lower specificity (84.0%, 95% CI 75.6–89.9) in HIV-infected patients with CD4 count less than 50/mm3. The sensitivity of the combined LF-LAM or sputum microscopy was higher than that of either test alone (86.1% vs. 75.0%, 61.1%, respectively). Mycobacterium avium complex (MAC) was cultured in 7 out of 20 with false positive result. Urine LAM strip test can remain positive for up to 4 weeks even after anti-TB treatment. Conclusion Urine LAM assay gave the best performance for diagnosis of active TB in advanced HIV-infected patients and provide an additional benefit of a greater simplicity, speed, with a more easily obtainable sample. Disclosures All authors: No reported disclosures.

Sensitivity and specificity of QuantiFERON-TB Gold Plus compared with QuantiFERON-TB Gold In-Tube and T-SPOT.TB on active tuberculosis in Japan.

PubMed

Takasaki, Jin; Manabe, Toshie; Morino, Eriko; Muto, Yoshikazu; Hashimoto, Masao; Iikura, Motoyasu; Izumi, Shinyu; Sugiyama, Haruhito; Kudo, Koichiro

2018-03-01

The QuantiFERON-TB Gold Plus (QFT-Plus) was introduced in 2015 as a new generation of interferon-gamma release assays (IGRAs) designed to detect Mycobacterium tuberculosis infection (TB). Examination of its diagnostic accuracy is crucial before it is launched in Japan. We examined 99 patients with laboratory-confirmed active TB (patients) and 117 healthy volunteers with no risk of TB infection (controls) at a medical center in Tokyo, Japan. Blood samples were collected from both the patients and controls and tested using three types of IGRAs: the QFT-Plus, the QuantiFERON-TB Gold In-Tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). The sensitivity and specificity of each IGRA were examined and compared. The sensitivity of the QFT-Plus was 98.9% (95% confidence interval [CI], 0.934-0.998) and similar to that of the QFT-GIT (97.9%; 95% CI, 0.929-0.998) and T-SPOT (96.9%; 95% CI, 0.914-0.994). The specificity of the QFT-Plus was the same as that of the QFT-GIT and T-SPOT (98.1%; 95% CI, 0.934-0.998). One patient with uncontrolled diabetes mellitus showed negative results on all three IGRAs. The QFT-Plus showed a high degree of agreement with the QFT-GIT and T-SPOT, with high sensitivity and specificity. Severe diabetes mellitus may influence the results of IGRAs. Larger studies are needed to validate the accuracy of the GFT-Plus and determine whether it can contribute as adjunctive method for the early diagnosis of active TB in Japan. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Social leverage of intellectual property: road to the development of better therapy for tuberculosis.

PubMed

Thangaraj, Harry; Reljic, Rajko

2009-06-01

Current TB drug development is beset with many problems. There is a perceived lack of commercial return on investment, as the vast majority of TB patients come from impoverished areas of the world. Clinical trials for new TB drugs are complex, protracted and very expensive. Therefore, the development of new anti-tuberculosis drugs requires simultaneous forward planning of the design of the trials that will be required for licensing purposes. In this article we briefly review the current state of new TB drug development and discuss issues related to intellectual property (IP), with a special emphasis on how IP can facilitate rather than hinder the development of better TB drugs. We also list and discuss the major patent applications that underpin TB drugs that have entered prominent clinical trials and additional applications that were filed over the last five years for drugs resulting from basic upstream research.

A Data-Driven Evaluation of the Stop TB Global Partnership Strategy of Targeting Key Populations at Greater Risk for Tuberculosis

PubMed Central

Schnippel, Kathryn; Sharp, Alana

2016-01-01

Objective Identifying those infected with tuberculosis (TB) is an important component of any strategy for reducing TB transmission and population prevalence. The Stop TB Global Partnership recently launched an initiative with a focus on key populations at greater risk for TB infection or poor clinical outcomes, due to housing and working conditions, incarceration, low household income, malnutrition, co-morbidities, exposure to tobacco and silica dust, or barriers to accessing medical care. To achieve operational targets, the global health community needs effective, low cost, and large-scale strategies for identifying key populations. Using South Africa as a test case, we assess the feasibility and effectiveness of targeting active case finding to populations with TB risk factors identified from regularly collected sources of data. Our approach is applicable to all countries with TB testing and census data. It allows countries to tailor their outreach activities to the particular risk factors of greatest significance in their national context. Methods We use a national database of TB test results to estimate municipality-level TB infection prevalence, and link it to Census data to measure population risk factors for TB including rates of urban households, informal settlements, household income, unemployment, and mobile phone ownership. To examine the relationship between TB prevalence and risk factors, we perform linear regression analysis and plot the set of population characteristics against TB prevalence and TB testing rate by municipality. We overlay lines of best fit and smoothed curves of best fit from locally weighted scatter plot smoothing. Findings Higher TB prevalence is statistically significantly associated with more urban municipalities (slope coefficient β1 = 0.129, p < 0.0001, R2 = 0.133), lower mobile phone access (β1 = -0.053, p < 0.001, R2 = 0.089), lower unemployment rates (β1 = -0.020, p = 0.003, R2 = 0.048), and a lower proportion of low-income households (β1 = -0.048, p < 0.0001, R2 = 0.084). Municipalities with more low-income households also have marginally higher TB testing rates, however, this association is not statistically significant (β1 = -0.025, p = 0.676, R2 = 0.001). There is no relationship between TB prevalence and the proportion of informal settlement households (β1 = 0.021, p = 0.136, R2 = 0.014). Conclusions These analyses reveal that the set of characteristics identified by the Global Plan as defining key populations do not adequately predict populations with high TB burden. For example, we find that higher TB prevalence is correlated with more urbanized municipalities but not with informal settlements. We highlight several factors that are counter-intuitively those most associated with high TB burdens and which should therefore play a large role in any effective targeting strategy. Targeting active case finding to key populations at higher risk of infection or poor clinical outcomes may prove more cost effective than broad efforts. However, these results should increase caution in current targeting of active case finding interventions. PMID:27732606

A Data-Driven Evaluation of the Stop TB Global Partnership Strategy of Targeting Key Populations at Greater Risk for Tuberculosis.

PubMed

McLaren, Zoë M; Schnippel, Kathryn; Sharp, Alana

2016-01-01

Identifying those infected with tuberculosis (TB) is an important component of any strategy for reducing TB transmission and population prevalence. The Stop TB Global Partnership recently launched an initiative with a focus on key populations at greater risk for TB infection or poor clinical outcomes, due to housing and working conditions, incarceration, low household income, malnutrition, co-morbidities, exposure to tobacco and silica dust, or barriers to accessing medical care. To achieve operational targets, the global health community needs effective, low cost, and large-scale strategies for identifying key populations. Using South Africa as a test case, we assess the feasibility and effectiveness of targeting active case finding to populations with TB risk factors identified from regularly collected sources of data. Our approach is applicable to all countries with TB testing and census data. It allows countries to tailor their outreach activities to the particular risk factors of greatest significance in their national context. We use a national database of TB test results to estimate municipality-level TB infection prevalence, and link it to Census data to measure population risk factors for TB including rates of urban households, informal settlements, household income, unemployment, and mobile phone ownership. To examine the relationship between TB prevalence and risk factors, we perform linear regression analysis and plot the set of population characteristics against TB prevalence and TB testing rate by municipality. We overlay lines of best fit and smoothed curves of best fit from locally weighted scatter plot smoothing. Higher TB prevalence is statistically significantly associated with more urban municipalities (slope coefficient β1 = 0.129, p < 0.0001, R2 = 0.133), lower mobile phone access (β1 = -0.053, p < 0.001, R2 = 0.089), lower unemployment rates (β1 = -0.020, p = 0.003, R2 = 0.048), and a lower proportion of low-income households (β1 = -0.048, p < 0.0001, R2 = 0.084). Municipalities with more low-income households also have marginally higher TB testing rates, however, this association is not statistically significant (β1 = -0.025, p = 0.676, R2 = 0.001). There is no relationship between TB prevalence and the proportion of informal settlement households (β1 = 0.021, p = 0.136, R2 = 0.014). These analyses reveal that the set of characteristics identified by the Global Plan as defining key populations do not adequately predict populations with high TB burden. For example, we find that higher TB prevalence is correlated with more urbanized municipalities but not with informal settlements. We highlight several factors that are counter-intuitively those most associated with high TB burdens and which should therefore play a large role in any effective targeting strategy. Targeting active case finding to key populations at higher risk of infection or poor clinical outcomes may prove more cost effective than broad efforts. However, these results should increase caution in current targeting of active case finding interventions.

Synthesis and evaluation of 4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] analogues against both active and dormant Mycobacterium tuberculosis.

PubMed

Alluri, Kiran Kumar; Reshma, Rudraraju Srilakshmi; Suraparaju, Raghuram; Gottapu, Suryanarayana; Sriram, Dharmarajan

2018-05-01

Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl)sulfonyl)-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8.23 µM) in active TB and was less effective than the lead but more potent than standard first line drug ethambutol. It was also found to be more efficacious than Isoniazid and Rifampicin and equipotent as Moxifloxacin against dormant Mycobacterium tuberculosis (MTB). Compound 06 also showed good inhibitory potential against over expressed latent MTB enzyme lysine ε-amino transferase with an IC 50 of 1.04 ± 0.32 µM. This compound is a good candidate for drug development owing to potential against both active and dormant stages of MTB. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of the food supplement Nyaditum resae as a new tool to reduce the risk of tuberculosis development.

PubMed

Tukvadze, Nestani; Cardona, Paula; Vashakidze, Sergo; Shubladze, Natalia; Avaliani, Zaza; Vilaplana, Cris; Cardona, Pere-Joan

2016-12-01

Nyaditum resae (NR) is a galenic preparation of heat-killed Mycobacterium manresensis (hkMn). This is a new species that belongs to the Mycobacterium fortuitum complex, and it is present in drinking water-thus, regulatorily speaking, it is considered a food supplement. Preclinical studies in the murine model of active tuberculosis (TB) in the C3HeB/FeJ strain have demonstrated that daily administration of NR containing 10 3 -10 6 hkMn for 14days was able to stop the progression toward active TB [1]. The mechanism of action was linked to the induction of low dose tolerance and was related to the increase of Tuberculin Purified Protein Derivative (PPD) memory-specific Tregs (CD4 + CD25 + CD39 + cells) after ex vivo incubation of splenocytes for 7days. This increase of Tregs was related to the increase of interleukin (IL)-10 in the spleen and in the reduction of IL-17 in the lungs, where there was also a reduction in bacillary load and the pathology caused by a reduction of neutrophiles' infiltration [2]. Two randomized, double-blind placebo-controlled clinical trials (CTs) have been conducted in humans. The NYADATREG study (Clinicaltrials.gov identifier NCT02076139; 2013-2014) was aimed to evaluate the safety and the immunogenicity of two concentrations of NR (containing 10 4 hkMn and 10 5 hkMn) versus placebo (all administered orally everyday for 14days) in tuberculin-positive and tuberculin-negative volunteers (total n=51). The results demonstrated an excellent safety record, with no differences between groups in terms of adverse effects. A significant increase in PPD-specific memory regulatory T cells was also detected in both NR groups [3]. The NYADAPETRICS study (Clinicaltrials.gov identifier NCT02581579) is evaluating the safety and immunogenicity of NR 10 5 hkMn (capsule format, orally) in the pediatric population. Currently, an efficacy study (randomized, double-blinded, placebo-controlled CT) is being conducted in Georgia. This NYADAGEORG trial includes close contacts of active TB cases with positive sputum not tributaries of chemoprophylaxis (<5-year-old children and HIV-positive individuals), which will receive NR (containing 10 5 hkMn) or placebo (orally, every day for 14days). A total of 3300 participants will be recruited in four medical centers around Tbilissi. The participants are monitored by telephone for up to 2years to evaluate the incidence of active TB. The hypothesis is that the NR group will exhibit a 40% reduction in expected TB incidence. Thus, the anticipated TB incidence will be 3% in the NR group versus 5% in the placebo group. The CT is projected to end by 2021 (Clinicaltrials.gov identifier NCT02897180). The administration of the food supplement NR appears to be a new, easy, safe, and reliable method for reducing the risk of developing active TB, and new CTs must be encouraged to discern the particular efficacy power according to different population characteristics. Copyright © 2016.

Development and Initial Testing of Messages to Encourage Tuberculosis Testing and Treatment Among Bacille Calmette-Guerin (BCG) Vaccinated Persons

PubMed Central

Galindo-Gonzalez, Sebastian; Irani, Tracy A.

2017-01-01

Misperceptions surrounding the Bacille Calmette-Guerin (BCG) vaccine can lead some vaccinated individuals to resist being tested and treated for tuberculosis (TB). Educational messages to best explain the risk of TB to BCG-vaccinated, Hispanic persons were systematically developed and tested. First, TB program staff provided messages they considered effective. These were analyzed and validated by TB experts, and then presented in group interviews initially to foreign-born Hispanic persons with a TB diagnosis, and then persons without a prior TB diagnosis. Based on interviewees’ feedback, preferred statements were used to develop one long and three short comprehensive messages. One-on-one interviews were conducted with Hispanic persons to assess the saliency of the comprehensive educational messages. Participants preferred messages that were gain or positively-framed and explained that BCG does not confer lifelong protection against TB. Participants confirmed the messages would likely have a positive impact on patient decisions to undergo TB testing and treatment. PMID:24141428

TB tracer teams in South Africa: knowledge, practices and challenges of tracing TB patients to improve adherence

PubMed Central

2013-01-01

Background In 2008–2009 the South African National Tuberculosis (TB) Program (NTP) implemented a national pilot project, the TB Tracer Project, aiming to decrease default rates and improve patient outcomes. The current study aimed to inform the NTP by describing the knowledge, attitudes, and practices of TB program personnel involved with tracing activities. Methods A self-administered written questionnaire was sent to TB staff, managers and tracer team leaders to assess basic TB knowledge, attitudes and practices. Descriptive statistics were used to summarize results and the chi-squared statistic was used to compare responses of staff at facilities that participated in the TB Tracer Project (tracer) and those that followed standard NTP care (non-tracer). Results Of 560 total questionnaires distributed, 270 were completed and returned (response rate 48%). Total TB knowledge ranged from 70.8-86.3% correct across all response groups. However, just over half (range 50–59.3%) of each respondent group was able to correctly identify the four components of a DOT encounter. A patient no longer feeling sick was cited by 72.1% of respondents as the reason patients fail to adhere to treatment. Tracer teams were viewed as an effective means to get patients to return to treatment by 96.3% of health facility level respondents. Tracer team leaders reported concerns including lack of logistical support (41.7%), insufficient physical safety precautions (41.7%), and inadequate protection from contracting TB (39.1%). Upon patients returning to treatment at the clinic, facilities included in the TB Tracer Project were significantly more likely to discuss alternate DOTS arrangements than non-tracer facilities (79.2 vs. 66.4%, p = 0.03). Conclusions This study identified key components of knowledge, attitudes, and practices regarding TB patient tracing activities in South Africa. Educating patients on the essential need to complete treatment irrespective of clinical symptoms may help improve treatment adherence. Future scale-up and integration of TB tracing activities as part of standard TB management should include provisions for standardized training of personnel on the critical elements of DOTS, and for ensuring appropriate supervision, logistical support, and physical safety and TB transmission protection of tracing teams. PMID:24007294

Detection of interleukin-2 is not useful for distinguishing between latent and active tuberculosis in clinical practice: a prospective cohort study.

PubMed

Santin, M; Morandeira-Rego, F; Alcaide, F; Rabuñal, R; Anibarro, L; Agüero-Balbín, R; Casas-Garcia, X; Pérez-Escolano, E; Navarro, M D; Sánchez, F; Coira-Nieto, A; Trigo-Daporta, M; Martinez-Meñaca, A; Gonzalez-Cuevas, A; López-Prieto, M D; Domínguez-Castellano, A; Jové, N

2016-12-01

Previous reports have identified interleukin-2 (IL-2), quantified in the supernatants of QuantiFERON ® -TB Gold In-tube (QFT) after 72 h of incubation, as a potential biomarker for distinguishing between latent and active tuberculosis (TB). However, its validity has not been tested in an appropriate clinical cohort. A multicentre study of 161 consecutive adult patients undergoing evaluation for active TB at eight TB Units in Spain. Interferon-γ (IFN-γ) and IL-2 were assessed in the supernatant of QFT after 16-24 h and 72 h of incubation. The accuracy of IL-2 for indicating latent TB infection (LTBI) was assessed by receiving operating characteristic curves. . Twenty-eight participants were not infected, 43 had LTBI, 69 had TB, and 21 were not classifiable. Median (interquartile range) IL-2 concentrations after 72 h of incubation were 0.0 pg/mL (0.0-0.0) in uninfected individuals, 261.0 pg/mL (81.0-853.0) in LTBI individuals, 166.5 pg/mL (33.5-551.5) in patients with extrapulmonary TB, 95.0 pg/mL (26.0-283.0) in patients with smear-negative pulmonary TB, and 38.5 pg/mL (7.5-178.0) in patients with smear-positive pulmonary TB (p <0.0001). The area under the curve of the receiving operating characteristic curve (95% CI) of IL-2 after 72 h of incubation for the diagnosis of LTBI was 0.63 (0.53-0.74) when all TB cases were considered as a single group, ranging from 0.59 (0.47-0.71) to 0.72 (0.58-0.85) when only extrapulmonary and smear-positive pulmonary TB cases respectively were considered. Quantification of IL-2 in the supernatant of QFT after a prolonged incubation is not useful to distinguish between LTBI and active disease in clinical practice. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Assessment of the influence of direct tobacco smoke on infection and active TB management

PubMed Central

Jiménez-Fuentes, María Ángeles; Maldonado, José; Molina, Israel; González-Díaz, Yoel; Milà, Celia; García-García, Esther; Muriel, Beatriz; Villar-Hernández, Raquel; Laabei, Maisem; Gómez, Andromeda-Celeste; Godoy, Pere; de Souza-Galvão, Maria Luiza; Solano, Segismundo; Jiménez-Ruiz, Carlos A.

2017-01-01

Background Smoking is a risk factor for tuberculosis (TB) infection and disease progression. Tobacco smoking increases susceptibility to TB in a variety of ways, one of which is due to a reduction of the IFN-γ response. Consequently, an impaired immune response could affect performance of IFN-γ Release Assays (IGRAs). Objective In the present study, we assess the impact of direct tobacco smoking on radiological manifestations, sputum conversion and immune response to Mycobacterium tuberculosis, analyzing IFN-γ secretion by IGRAs. Methods A total of 525 participants were studied: (i) 175 active pulmonary TB patients and (ii) 350 individuals coming from contact tracing studies, 41 of whom were secondary TB cases. Clinical, radiological and microbiological data were collected. T-SPOT.TB and QFN-G-IT were processed according manufacturer’s instructions. Results In smoking patients with active TB, QFN-G-IT (34.4%) and T-SPOT.TB (19.5%) had high frequencies of negative results. In addition, by means of an unconditional logistic regression, smoking was a main factor associated with IGRAs’ false-negative results (aOR: 3.35; 95%CI:1.47–7.61; p<0.05). Smoking patients with active TB presented a high probability of having cavitary lesions (aOR: 1.88; 95%CI:1.02–3.46;p<0.05). Mean culture negativization (months) ± standard deviation (SD) was higher in smokers than in non-smokers (2.47±1.3 versus 1.69±1.4). Latent TB infection (LTBI) was favored in smoking contacts, being a risk factor associated with infection (aOR: 11.57; 95%CI:5.97–22.41; p<0.00005). The IFN-γ response was significantly higher in non-smokers than in smokers. Smoking quantity and IFN-γ response analyzed by IGRAs were dose-dependent related. Conclusions Smoking had a negative effect on radiological manifestations, delaying time of sputum conversion. Our data establish a link between tobacco smoking and TB due to a weakened IFN-γ response caused by direct tobacco smoke. PMID:28837570

Challenges with diagnosing and investigating suspected active tuberculosis disease in military trainees.

PubMed

Chang, David; Webber, Bryant J; Hetrick, Steven M; Owen, Jerry B; Blasi, Audra A; Steele, Bernadette M; Yun, Heather C

2017-08-01

Between 1 January 2010 and 31 December 2016, a total of 14 U.S. and international military personnel in training at Joint Base San Antonio-Lackland, TX, were hospitalized due to suspected pulmonary tuberculosis (TB); of these, five personnel were diagnosed with active TB disease. Only one TB case had pulmonary symptoms, but these symptoms were not suggestive of TB. The incidence rate in the training population was 1.89 per 100,000 population (95% CI: 0.81, 4.42), with a higher rate when restricted to international military students attending the Defense Language Institute English Language Center. No instances of TB transmission were identified. The variety of atypical presentations and their resulting diagnostic and public health challenges prompted this retrospective review of all hospitalized cases. This case series highlights both the importance of a high index of clinical suspicion when TB is being considered in close congregate settings as well as the risk of overreliance on acid-fast bacilli staining and nucleic acid amplification testing for ruling out active pulmonary disease in young, otherwise healthy trainees. Practical solutions are suggested.

A world of cities and the end of TB

PubMed Central

Prasad, Amit; Ross, Alex; Rosenberg, Paul; Dye, Christopher

2016-01-01

The WHO's End TB Strategy aims to reduce TB deaths by 95% and incidence by 90% between 2015 and 2035. As the world rapidly urbanizes, more people could have access to better infrastructure and services to help combat poverty and infectious diseases, including TB. And yet large numbers of people now live in overcrowded slums, with poor access to urban health services, amplifying the burden of TB. An alignment of the Sustainable Development Goals (SDGs) for health and for urban development provides an opportunity to accelerate the overall decline in infection and disease, and to create cities free of TB. PMID:26884491

Enhancing the role of private practitioners in tuberculosis prevention and care activities in India.

PubMed

Anand, Tanu; Babu, Ranjith; Jacob, Anil G; Sagili, Karuna; Chadha, Sarabjit S

2017-01-01

India accounts for the highest number of incident tuberculosis (TB) cases globally. Hence, to impact the TB incidence world over, there is an urgent need to address and accelerate TB control activities in the country. Nearly, half of the TB patients first seek TB care in private sector. However, the participation of private practitioners (PPs) has been patchy in TB prevention and care and distrust exists between public and private sector. PPs usually have varied diagnostic and treatment practices that are inadequate and amplify the risk of drug resistance. Hence, their regulation and involvement as key stakeholders are important in TB prevention and care in India if we are to achieve TB control at global level. However, there remain certain barriers and gaps, which are preventing their upscaling. The current paper aims to discuss the status of private sector involvement in TB prevention and care in India. The paper also discusses the strategies and initiatives taken by the government in this regard as evidence shows that the involvement of private sector in co-opting directly observed treatment short-course (DOTS) helps to enhance case finding and treatment outcomes; it improves the accessibility of quality TB care with greater geographic coverage. Besides public-private mix, DOTS has been found more cost-effective and reduces financial burden of patients. The paper also offers to present some more solutions both at policy and program level for upscaling the engagement of PPs in the national TB control program.

Enhancing the role of private practitioners in tuberculosis prevention and care activities in India

PubMed Central

Anand, Tanu; Babu, Ranjith; Jacob, Anil G.; Sagili, Karuna; Chadha, Sarabjit S.

2017-01-01

India accounts for the highest number of incident tuberculosis (TB) cases globally. Hence, to impact the TB incidence world over, there is an urgent need to address and accelerate TB control activities in the country. Nearly, half of the TB patients first seek TB care in private sector. However, the participation of private practitioners (PPs) has been patchy in TB prevention and care and distrust exists between public and private sector. PPs usually have varied diagnostic and treatment practices that are inadequate and amplify the risk of drug resistance. Hence, their regulation and involvement as key stakeholders are important in TB prevention and care in India if we are to achieve TB control at global level. However, there remain certain barriers and gaps, which are preventing their upscaling. The current paper aims to discuss the status of private sector involvement in TB prevention and care in India. The paper also discusses the strategies and initiatives taken by the government in this regard as evidence shows that the involvement of private sector in co-opting directly observed treatment short-course (DOTS) helps to enhance case finding and treatment outcomes; it improves the accessibility of quality TB care with greater geographic coverage. Besides public-private mix, DOTS has been found more cost-effective and reduces financial burden of patients. The paper also offers to present some more solutions both at policy and program level for upscaling the engagement of PPs in the national TB control program. PMID:29099000

Integrating HIV testing and care into tuberculosis services in Benin: programmatic aspects.

PubMed

Ferroussier, O; Dlodlo, R A; Capo-Chichi, D; Boillot, F; Gninafon, M; Trébucq, A; Fujiwara, P I

2013-11-01

Between 2005 and 2008, the diagnosis and care of human immunodeficiency virus (HIV) infection and tuberculosis (TB) services were integrated in Benin. The appointment of a TB-HIV Coordinator by the National Tuberculosis Control Programme and quarterly supervisory visits to TB clinics have bolstered the implementation of integrated HIV-TB activities. HIV testing and cotrimoxazole preventive therapy were integrated smoothly into the TB services. The strategy chosen to facilitate access of HIV-positive TB patients to antiretroviral treatment contributed to greater integration over time, but perpetuated, for some, the burden of attending two facilities. The integration and decentralisation of TB and HIV care services at national level in Benin resulted in a high uptake of HIV services among TB patients.

Prospective Comparison of QFT-GIT and T-SPOT.TB Assays for Diagnosis of Active Tuberculosis.

PubMed

Du, Fengjiao; Xie, Li; Zhang, Yonghong; Gao, Fei; Zhang, Huibin; Chen, Wei; Sun, Bingqi; Sha, Wei; Fang, Yong; Jia, Hongyan; Xing, Aiying; Du, Boping; Zheng, Li; Gao, Mengqiu; Zhang, Zongde

2018-04-12

T-SPOT.TB and QuantiFERON-TB Gold In-Tube (QFT-GIT) tests, as two commercial blood assays for diagnosing active tuberculosis (ATB), are not yet fully validated. Especially, there are no reports on comparing the efficacy between the two tests in the same population in China. A multicenter, prospective comparison study was undertaken at four hospitals specializing in pulmonary diseases. A total of 746 suspected pulmonary TB were enrolled and categorized, including 185 confirmed TB, 298 probable TB and 263 non-TB. Of 32 patients with indeterminate test results (ITRs), age and underlying disease were associated with the rate of ITRs. Furthermore, the rate of ITRs determined by T-SPOT.TB was lower than QFT-GIT (0.4% vs. 4.3%, P < 0.01). When excluding ITRs, the sensitivities of T-SPOT.TB and QFT-GIT were 85.2% and 84.8%, and specificities of 63.4% and 60.5%, respectively in the diagnosis of ATB. The two assays have an overall agreement of 92.3%, but exhibited a poor linear correlation (r 2  = 0.086) between the levels of interferon-γ release detected by the different assays. Although having some heterogeneity in detecting interferon-γ release, both the QFT-GIT and T-SPOT.TB demonstrated high concordance in diagnosing ATB. However, neither of them showed suitability in the definitive diagnosis of the disease.

Implementing the End TB Strategy in the Western Pacific Region: Translating vision into reality.

PubMed

Rahevar, Kalpeshsinh; Fujiwara, Paula I; Ahmadova, Shalala; Morishita, Fukushi; Reichman, Lee B

2018-04-12

The End TB Strategy aims to end the global tuberculosis (TB) epidemic by 2035 in line with the sustainable development goals targets and has been implemented in the World Health Organization (WHO) Western Pacific Region since 2015. Significant progress has been made in implementing this strategy. However, several challenges still remain. In 2016, an estimated 1.8 million people developed TB in the region, and of these about 20% were missed by national TB programmes. The gap in diagnosis and enrolment as well as treatment completion is greater with drug-resistant TB. Many TB-affected families face catastrophic costs due to the disease. Sustaining financing for TB care is a long-term challenge in many countries. This article emphasizes targeted interventions in high-risk populations, including systematic screening and patient-centred TB care. Several other approaches including improving TB diagnostic tools and algorithm, and engaging all care providers are suggested to find missing TB patients. Drug-resistant TB requires additional resourcing for laboratories, enrolment and patient support. Specific measures are required at different levels to mitigate financial burden due to TB including linking TB to overall social protection schemes. The Moscow Ministerial conference in 2017 and upcoming United Nations (UN) 2018 high-level meeting provide an opportunity to raise TB higher on the global agenda, forge partnerships and move towards universal health coverage. © 2018 Asian Pacific Society of Respirology.

Developing a tuberculosis transmission model that accounts for changes in population health.

PubMed

Oxlade, Olivia; Schwartzman, Kevin; Benedetti, Andrea; Pai, Madhukar; Heymann, Jody; Menzies, Dick

2011-01-01

Simulation models are useful in policy planning for tuberculosis (TB) control. To accurately assess interventions, important modifiers of the epidemic should be accounted for in evaluative models. Improvements in population health were associated with the declining TB epidemic in the pre-antibiotic era and may be relevant today. The objective of this study was to develop and validate a TB transmission model that accounted for changes in population health. We developed a deterministic TB transmission model, using reported data from the pre-antibiotic era in England. Change in adjusted life expectancy, used as a proxy for general health, was used to determine the rate of change of key epidemiological parameters. Predicted outcomes included risk of TB infection and TB mortality. The model was validated in the setting of the Netherlands and then applied to modern Peru. The model, developed in the setting of England, predicted TB trends in the Netherlands very accurately. The R(2) value for correlation between observed and predicted data was 0.97 and 0.95 for TB infection and mortality, respectively. In Peru, the predicted decline in incidence prior to the expansion of "Directly Observed Treatment Short Course" (The DOTS strategy) was 3.7% per year (observed = 3.9% per year). After DOTS expansion, the predicted decline was very similar to the observed decline of 5.8% per year. We successfully developed and validated a TB model, which uses a proxy for population health to estimate changes in key epidemiology parameters. Population health contributed significantly to improvement in TB outcomes observed in Peru. Changing population health should be incorporated into evaluative models for global TB control.

Alveolar Epithelial Cells in Mycobacterium tuberculosis Infection: Active Players or Innocent Bystanders?

PubMed

Scordo, Julia M; Knoell, Daren L; Torrelles, Jordi B

2016-01-01

Tuberculosis (TB) is a disease that kills one person every 18 s. TB remains a global threat due to the emergence of drug-resistant Mycobacterium tuberculosis (M.tb) strains and the lack of an efficient vaccine. The ability of M.tb to persist in latency, evade recognition following seroconversion, and establish resistance in vulnerable populations warrants closer examination. Past and current research has primarily focused on examination of the role of alveolar macrophages and dendritic cells during M.tb infection, which are critical in the establishment of the host response during infection. However, emerging evidence indicates that the alveolar epithelium is a harbor for M.tb and critical during progression to active disease. Here we evaluate the relatively unexplored role of the alveolar epithelium as a reservoir and also its capacity to secrete soluble mediators upon M.tb exposure, which influence the extent of infection. We further discuss how the M.tb-alveolar epithelium interaction instigates cell-to-cell crosstalk that regulates the immune balance between a proinflammatory and an immunoregulatory state, thereby prohibiting or allowing the establishment of infection. We propose that consideration of alveolar epithelia provides a more comprehensive understanding of the lung environment in vivo in the context of host defense against M.tb. © 2015 S. Karger AG, Basel.

Alveolar epithelial cells in Mycobacterium tuberculosis infection: Active Players or Innocent Bystanders

PubMed Central

Scordo, Julia M.; Knoell, Daren L.; Torrelles, Jordi B.

2015-01-01

Tuberculosis (TB) is a disease that kills one person every 18 seconds. TB remains a global threat due to the emergence of drug resistance Mycobacterium tuberculosis (M.tb) strains and the lack of an efficient vaccine. The ability of M.tb to persist in latency, evade recognition following sero-conversion and establish resistance in vulnerable populations warrants closer examination. Past and current research has primarily focused on examination of the role of alveolar macrophages and dendritic cells during M.tb infection, which are critical in the establishment of the host response during infection. However, emerging evidence indicates that the alveolar epithelium is a harbor for M.tb and critical during progression to active disease. Here we evaluate the relatively unexplored role of the alveolar epithelium as a reservoir and also its capacity to secrete soluble mediators upon M.tb exposure that influence the extent of infection. We further discuss how the M.tb-alveolar epithelia interaction instigate cell to cell crosstalk that regulates immune balance between a pro-inflammatory or immunoregulatory state thereby prohibiting or allowing the establishment of infection. We propose that consideration of the alveolar epithelia provides a more comprehensive understanding of the lung environment in vivo in the context of host defense against M.tb. PMID:26384325

Strengthening TB infection control in specialized health facilities in Romania--using a participatory approach.

PubMed

Turusbekova, N; Popa, C; Dragos, M; van der Werf, M J; Dinca, I

2016-02-01

In 2012, the tuberculosis (TB) notification rate among Romanian TB facility doctors and nurses was 7.2 times higher than in the general population. This indicates that transmission is ongoing inside TB facilities and that TB infection control measures are insufficient. To help prevent nosocomial TB transmission a project was implemented that aimed at providing nationwide tailor-made technical assistance in TB infection control (TB-IC) in TB treatment facilities, including the development of TB infection control plans. The objective of the present article is to describe the implementation of the project and to discuss successes and challenges. The project was an implementation study using two methods of evaluation: (1) a cross sectional questionnaire study; and (2) collection of information, during the training, on challenges related to infection control and to the project implementation. The project team developed a TB facility infection control (TB-IC) plan template, together with the Romanian experts. The template was discussed and agreed upon with the experts at a meeting and thereafter distributed by email to all TB facilities. Afterwards, a training of trainers (TOT) seminar was organized which included the provision of information about different training methods, as well as information about TB-IC. The TOT was followed by training for key TB-IC providers. Information about use of the TB-IC template was gathered through a self-administered questionnaire sent to all participants of the expert meeting and the training (42 people). Additionally, non-systematized discussions were held on broader challenges in TB-IC implementation during the training. Within the project 42 key TB-IC service providers were trained in TB-IC, including 9 who were trained at a TOT seminar. The trainees were specialists working at the national level, such as country TB coordinators, or at the TB facility level: TB doctors, epidemiologists, laboratory specialists and maintenance engineers. Out of 42 key TB-IC service providers who were trained, only eighteen responded to the questionnaire (no reminders were sent). Out of these, 14 had used the TB-IC plan template after the project team disseminated it to them by email. The remaining four TB-IC service providers indicated that they were planning to use the template to develop or update their facility TB-IC plans. Related to the use of TB-IC plan template, the following broader challenges in TB-IC were identified: a lack of authority of the individuals responsible for TB-IC to implement the TB-IC measures, lack of training among facility epidemiologists on TB, underdeveloped system for reporting TB in healthcare workers, difficulties with triage of the TB suspects, and poor facility infrastructure hampering implementation of TB-IC measures. Implementing TB-IC plans in Romanian health care facilities proved to be challenging, mainly due to the fact that the national infection control plan for TB was not yet adopted at the time of project implementation, and therefore there was neither a regulatory framework to support TB facility-IC planning nor any related budget allocations for the implementation of the facilities' TB-IC plans. Nonetheless, most respondents who answered the questionnaire (18 of 42 responded) indicated that they had started using the TB-IC plan template, which represents a full package of infection control measures that, when implemented effectively and in its entirety, may be expected to reduce nosocomial transmission. The study's limitations are: very low survey response rate, thus there is a likelihood of responder bias. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Estimating tuberculosis incidence from primary survey data: a mathematical modeling approach.

PubMed

Pandey, S; Chadha, V K; Laxminarayan, R; Arinaminpathy, N

2017-04-01

There is an urgent need for improved estimations of the burden of tuberculosis (TB). To develop a new quantitative method based on mathematical modelling, and to demonstrate its application to TB in India. We developed a simple model of TB transmission dynamics to estimate the annual incidence of TB disease from the annual risk of tuberculous infection and prevalence of smear-positive TB. We first compared model estimates for annual infections per smear-positive TB case using previous empirical estimates from China, Korea and the Philippines. We then applied the model to estimate TB incidence in India, stratified by urban and rural settings. Study model estimates show agreement with previous empirical estimates. Applied to India, the model suggests an annual incidence of smear-positive TB of 89.8 per 100 000 population (95%CI 56.8-156.3). Results show differences in urban and rural TB: while an urban TB case infects more individuals per year, a rural TB case remains infectious for appreciably longer, suggesting the need for interventions tailored to these different settings. Simple models of TB transmission, in conjunction with necessary data, can offer approaches to burden estimation that complement those currently being used.

[Tuberculosis control in Shinjuku Ward, Tokyo--promoting the DOTS program and its outcome].

PubMed

Kaguraoka, Sumi; Ohmori, Masako; Takao, Yoshiko; Yamada, Mari; Muroi, Masako; Nagamine, Michiko; Fukazawa, Keiji; Nagai, Megumi; Wada, Masako; Hoshino, Hitoshi; Yoshiyama, Takashi; Maeda, Hideo; Ishikawa, Nobukatsu

2008-09-01

The objectives were to report how to promote tuberculosis (TB) control including DOTS (Directly Observed Treatment, Short-course) programs, and to evaluate the results of TB control programs in Shinjuku Ward (Shinjuku-ku). SETTING AND CHARACTERISTICS: Inhabitants and TB patients in Shinjuku Ward. Shinjuku Ward is located in the center of metropolitan Tokyo and has typical urban TB problems, such as high incidence rate and TB among foreigners and the homeless. The TB incidence rates in Shinjuku Ward decreased from 83.9 per 100,000 population in 1999 to 42.5 per 100,000 population in 2006, however, the rates were still two times higher than the national average. Therefore, one of the important TB programs in Shinjuku has been to actively detect cases among high-risk groups such as foreigners and the homeless. We observed the trend of case detection rates by health examination with chest X-ray among different high-risk groups, and compared the treatment outcomes before and after DOTS program execution. We also reviewed the changes of re-treatment rates and drug resistance rates. The case detection rates of TB by health examinations of foreign students at Japanese language schools decreased from 0.49% in 1996 to 0.13% in 2006 (p = 0.021). Although the case detection rates decreased, they were still about 26 times higher than those of Japanese students. While, the case detection rates among the homeless remained high with 4.7%, 3.3%, 4.5% and 3.6% in 1999-2002, respectively, since 2003, however, they had decreased and no TB cases were detected in 2005-2006. The DOTS program for homeless TB patients has been carried out since 2000 and that for the foreigners since 2003. The rates of defaulting during treatment before DOTS were very high among both homeless patients (21.4%) and foreigners (29.8%) in 1998-1999. However, after the introduction of DOTS program, those rates declined to 10.4% (p = 0.014) among the homeless and 7.8% (p = 0.002) among foreigners in 2002-2004. The proportion of newly notified patients with previous TB treatment and those with multi-drug resistant TB (MDR-TB) have also decreased after the introduction of DOTS programs. From 2000-2002 to 2003-2006, the re-treatment rates decreased from 19.4% to 10.0% (p < 0.001) and MDR-TB rates decreased from 1.6% to 0.2% (p = 0.042), respectively. The key points of TB control in Shinjuku Ward are to detect TB cases early especially among the high-risk groups, and to assist all TB patients to complete their treatment. In order to expand this strategy, besides promoting active case findings among high-risk groups, we have developed many types of DOTS programs, considering each patient's lifestyle and cooperating with school teachers at schools, pharmacists at pharmacies, home-care specialists at homes or facilities for the elderly, and so on. Among others, a major premise for the homeless and some other socially disadvantaged patients was to guarantee the provision of medicine and living by introducing social welfare services, before starting DOTS programs. This approach might have helped to reduce the defaulting rate, relapse rate and MDR-TB rate.

IP-10 and MIG are compartmentalized at the site of disease during pleural and meningeal tuberculosis and are decreased after antituberculosis treatment.

PubMed

Yang, Qianting; Cai, Yi; Zhao, Wei; Wu, Fan; Zhang, Mingxia; Luo, Kai; Zhang, Yan; Liu, Haiying; Zhou, Boping; Kornfeld, Hardy; Chen, Xinchun

2014-12-01

The diagnosis of active tuberculosis (TB) disease remains a challenge, especially in high-burden settings. Cytokines and chemokines are important in the pathogenesis of TB. Here we investigate the usefulness of circulating and compartmentalized cytokines/chemokines for diagnosis of TB. The levels of multiple cytokines/chemokines in plasma, pleural fluid (PF), and cerebrospinal fluid (CSF) were determined by Luminex liquid array-based multiplexed immunoassays. Three of 26 cytokines/chemokines in plasma were significantly different between TB and latent tuberculosis infection (LTBI). Among them, IP-10 and MIG had the highest diagnostic values, with an area under the receiver operating characteristic curve (ROC AUC) of 0.92 for IP-10 and 0.86 for MIG for distinguishing TB from LTBI. However, IP-10 and MIG levels in plasma were not different between TB and non-TB lung disease. In contrast, compartmentalized IP-10 and MIG in the PF and CSF showed promising diagnostic values in discriminating TB and non-TB pleural effusion (AUC = 0.87 for IP-10 and 0.93 for MIG), as well as TB meningitis and non-TB meningitis (AUC = 0.9 for IP-10 and 0.95 for MIG). A longitudinal study showed that the plasma levels of IP-10, MIG, granulocyte colony-stimulating factor (G-CSF), and gamma interferon (IFN-γ) decreased, while the levels of MCP-1/CCL2 and eotaxin-1/CCL11 increased, after successful treatment of TB. Our findings provide a practical methodology for discriminating active TB from LTBI by sequential IFN-γ release assays (IGRAs) and plasma IP-10 testing, while increased IP-10 and MIG at the site of infection (PF or CSF) can be used as a marker for distinguishing pleural effusion and meningitis caused by TB from those of non-TB origins. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Tuberculosis among nonimmigrant visitors to US Military installations.

PubMed

Aaron, Christopher L; Fotinos, Meletios J; West, Kevin B; Goodwin, Donald J; Mancuso, James D

2013-03-01

Nonimmigrant visitors are not required to be evaluated for tuberculosis (TB) before entering the country. Little literature exists describing the challenges of TB control among this demographic. This report reviews the challenges in managing TB in this population on U.S. military installations. Six cases were identified from reportable medical event reports. Information was obtained from public health personnel via phone interviews. Verified cases from 2004 to 2011 were included. Challenges were congruent among locations including: lack of procedures to screen for infection and disease among individuals at time of entry allowing one case to be admitted with acquired immunodeficiency syndrome and another concurrently on treatment for active TB; delays in the diagnosis of active TB as median time from entry to diagnosis was 62 days; and the need to conduct an effective contact investigation as the mean contact index was 77 including 1 secondary case of active TB. These cases emphasize the need for screening for TB in visitors from high-risk countries at time of entry, prompt diagnosis and treatment if found, procedures for evaluation of contacts, and interjurisdictional cooperation in large contact investigations. These challenges are common to nonimmigrants in both military and civilian settings. Reprint & Copyright © 2013 Association of Military Surgeons of the U.S.

[Tuberculosis in Asia].

PubMed

2002-10-01

1. Philippines: The development, expansion and maintenance of pilot area activities: Cristina B. Giango (Technical Division, Cebu Provincial Health Office, the Philippines) In 1994, the Department of Health developed the new NTP policies based on WHO recommendations and started a pilot project in Cebu Province in collaboration with the Japan International Cooperation Agency. To test its feasibility and effectiveness, the new NTP policies were pre-tested in one city and one Rural Health Unit. The test showed a high rate of three sputum collection (90%), high positive rate (10%), and high cure rate (80%). Before the new guidelines were introduced, the new policy was briefed, a baseline survey of the facility was conducted, equipment was provided, and intensive training was given. Recording/Reporting forms and procedures were also developed to ensure accurate reporting. Supervision, an important activity to ensure effective performance, was institutionalized. Laboratory services were strengthened, and a quality-control system was introduced in 1995 to ensure the quality of the laboratory services. With the implementation of DOTS strategy, barangay health workers were trained as treatment partners. In partnership with the private sector, the TB Diagnostic Committee was organized to deliberate and assess sputum negative but X-ray positive cases. The implementation of the new NTP guidelines in Cebe Province has reached a satisfactory level, the cure rate and positive rate have increased, and laboratory services have improved. Because of its successful implementation, the new NTP guidelines are now being used nationwide. 2. Nepal: The DOTS Strategy in the area with hard geographic situation: Dirgh Singh Bam (National Tuberculosis Center, Nepal) Three groups of factors characterize the population of Nepal: 1) Socio-cultural factors, e.g. migration, poverty, language; 2) Environmental factors, e.g. geography and climate; and 3) Political factors, prisoners and refugee populations. These factors pose particular problems for implementing DOTS in various ways. Socio-cultural and environmental factors are particularly important in Nepal, and several measures have been developed to overcome these difficulties. One is active community participation through the DOTS committee. The committee consists of a group of motivated people, including social workers, political leaders, health services providers, journalists, teachers, students, representatives of local organizations, medical schools and colleges, industries, private practitioners, and TB patients. One DOTS committee is formed in every treatment center. A key role of the DOTS committee is to identify local problems and their solutions. It increases public awareness about TB and DOTS; supports people with TB in the community by providing treatment observers and tracing late patients; and encourages cooperation among health institutions, health workers, NGOs, and political leaders. The case finding rate is now 69%, and nearly 95% of diagnosed TB cases are being treated under DOTS. The treatment success rate of new smear-positive cases is nearly 90%. Thus, DOTS increases the case finding and treatment success. 3. Cambodia: HIV/TB and the health sector reform: Tan Eang Mao (National Center for Tuberculosis and Leprosy Control, Cambodia) Cambodia is one of the 23 high burden countries of tuberculosis in the world. Moreover, HIV/AIDS has been spreading rapidly since 1990s, which is worsening the tuberculosis epidemics. To cope with the burden, Cambodia has started implementation of DOTS in 1994 and has expanded it to most of public hospitals across the country by 1998. NTP of Cambodia is now enjoying high cure rate of more than 90%. However, due to the constraints such as weak infrastructure and the poverty, it is proved that many of TB sufferers do not have access to the TB services, resulting in still low case detection rate. It is for this reason that the NTP has decided to expand DOTS to health center and community level based on the new health system. Its pilot program that has been carried out in collaboration with JICA and WHO since 1999 has achieved promising results with high detection and cure rates. All of the over 900 health centers across the country will be involved in DOTS strategy by 2005. In the fight against TB/HIV, National Center for TB Control is providing free TB screening for PLWH (people living with HIV/AIDS), and it is developing a comprehensive plan of TB/HIV care including home delivery DOT services. 4. China: The World Bank Project and the Prevalence Survey in China: Hong Jin DuanMu (National Tuberculosis Control Center, China) Since 1992, China has utilized a World Bank loan to implement TB control projects among 560 million people in 13 provinces. Free diagnosis and treatment services have been provided to all patients, and a fully supervised standard short-course chemotherapy was applied to all diagnosed tuberculosis patients. In 1999, more than 190,000 smear-positive cases, ten times the number in 1992, were detected, and the registration rate of new cases reached 30 per 100,000 population. From 1992 to 1999, a total of 1.40 million smear-positive TB patients were discovered. The cure rate of smear-positive TB patients has been improved to an overall cure rate of 93.6%. The cure rates for the new cases and re-treatment patients were 95.1% and 89.6%, respectively. The fourth nationwide random survey for the epidemiology of tuberculosis was conducted in 2000. The prevalence of active tuberculosis was 367/100,000, the prevalence of infectious tuberculosis was 160/100,000, and the prevalence of smear-positive tuberculosis was 122/100,000. The tuberculosis mortality was 9.8/100,000. 5. Vietnam: The road to reaching the Global Target: Le Ba Tung (Pham Ngoc Thach Tuberculosis and Lung Disease Center, Vietnam) TB control activities started in 1957 and were reorganized in 1986 with the technical assistance of IUATLD, KNCV and material assistance of Medical Committee Netherlands Vietnam (MCNV). The New National TB Control Program follows the main directives of WHO and IUATLD's procedures of case-finding, chemotherapy and management. Passive case-findings are based on sputum smear. Chemotherapy with priority for smear positive cases is 3SHZ/6S2H2 for new cases and 3HRE/6H2R2E2 for retreated cases, which is undertaken with directly observed therapy (DOT strategy) mainly at commune health posts. Since 1989, DOTS strategy with 2SHRZ/6HE for new cases and 2SHRZE/1HRZE/5H3R3E3 for retreated cases has gradually been introduced in districts and communes of every province. In 1995, the government established the National and Provincial TB Control Steering Committees and has provided incentives for detected smear positive cases and cured smear positive cases. The government has also started strengthening the program of managerial and supervisory capacity for TB staff and has promoted the cooperation of all associated organizations of TB control. The WHO global surveillance and monitoring project reports that in 2000 Vietnam reached the global target, i.e., 99.8% population covered by DOTS with 80% of expected new smear positive cases being detected and a high cure rate ranging from 85.3% in 1989 to 90.3% in 1999. A distinguishing aspect of TB control in Vietnam is the effective international partnerships combined with high political commitment of the government nationally and provincially as well as active participation of all organizations in the community.

The experience of implementing a 'TB village' for a pastoralist population in Cherrati, Ethiopia.

PubMed

Tayler-Smith, K; Khogali, M; Keiluhu, K; Jemmy, J-P; Ayada, L; Weyeyso, T; Issa, A M; De Maio, G; Harries, A D; Zachariah, R

2011-10-01

In Cherrati District, Somali Regional State (SRS), Ethiopia, despite a high burden of tuberculosis (TB), TB control activities are virtually absent. The majority of the population is pastoralist with a mobile lifestyle. TB care and treatment were offered using a 'TB village' approach that included traditional style residential care, community empowerment and awareness raising, provision of essential social amenities and essential food and non-food items. To describe 1) key aspects of the implementation of the TB village approach, 2) TB treatment outcomes and 3) the lessons learnt during implementation. Descriptive study. A total of 297 patients entered the TB village between September 2006 and October 2008; 271 (91%) patients were treated successfully, nine (3%) defaulted and 13 (4%) died. For pastoralist populations, a TB village approach may be effective for improving access to TB care, ensuring proper adherence to treatment and achieving good overall TB outcomes. The successes and challenges of this approach are discussed.

The effectiveness and cost-effectiveness of screening for latent tuberculosis among migrants in the EU/EEA: a systematic review

PubMed Central

Greenaway, Christina; Pareek, Manish; Abou Chakra, Claire-Nour; Walji, Moneeza; Makarenko, Iuliia; Alabdulkarim, Balqis; Hogan, Catherine; McConnell, Ted; Scarfo, Brittany; Christensen, Robin; Tran, Anh; Rowbotham, Nick; van der Werf, Marieke J; Noori, Teymur; Pottie, Kevin; Matteelli, Alberto; Zenner, Dominik; Morton, Rachael L.

2018-01-01

Background Migrants account for a large and growing proportion of tuberculosis (TB) cases in low-incidence countries in the European Union/European Economic Area (EU/EEA) which are primarily due to reactivation of latent TB infection (LTBI). Addressing LTBI among migrants will be critical to achieve TB elimination. Methods: We conducted a systematic review to determine effectiveness (performance of diagnostic tests, efficacy of treatment, uptake and completion of screening and treatment) and a second systematic review on cost-effectiveness of LTBI screening programmes for migrants living in the EU/EEA. Results: We identified seven systematic reviews and 16 individual studies that addressed our aims. Tuberculin skin tests and interferon gamma release assays had high sensitivity (79%) but when positive, both tests poorly predicted the development of active TB (incidence rate ratio: 2.07 and 2.40, respectively). Different LTBI treatment regimens had low to moderate efficacy but were equivalent in preventing active TB. Rifampicin-based regimens may be preferred because of lower hepatotoxicity (risk ratio = 0.15) and higher completion rates (82% vs 69%) compared with isoniazid. Only 14.3% of migrants eligible for screening completed treatment because of losses along all steps of the LTBI care cascade. Limited economic analyses suggest that the most cost-effective approach may be targeting young migrants from high TB incidence countries. Discussion: The effectiveness of LTBI programmes is limited by the large pool of migrants with LTBI, poorly predictive tests, long treatments and a weak care cascade. Targeted LTBI programmes that ensure high screening uptake and treatment completion will have greatest individual and public health benefit. PMID:29637889

Pan-London tuberculosis services: a service evaluation

PubMed Central

2012-01-01

Background London has the largest proportion of tuberculosis (TB) cases of any western European capital, with almost half of new cases drug-resistant. Prevalence varies considerably between and within boroughs with research suggesting inadequate control of TB transmission in London. Economic pressures may exacerbate the already considerable challenges for service organisation and delivery within this context. This paper presents selected findings from an evaluation of London’s TB services’ organisation, delivery, professional workforce and skill mix, intended to support development of a strategic framework for a pan-London TB service. These may also interest health service professionals and managers in TB services in the UK, other European cities and countries and in services currently delivered by multiple providers operating independently. Methods Objectives were: 1) To establish how London’s TB services are structured and delivered in relation to leadership, management, organisation and delivery, coordination, staffing and support; 2) To identify tools/models for calculating skill mix as a basis for identifying skill mix requirements in delivering TB services across London; 3) To inform a strategic framework for the delivery of a pan-London TB service, which may be applicable to other European cities. The multi-method service audit evaluation comprised documentary analysis, semi-structured interviews with TB service users (n = 10), lead TB health professionals and managers (n = 13) representing London’s five sectors and focus groups with TB nurses (n = 8) and non-London network professionals (n = 2). Results Findings showed TB services to be mainly hospital-based, with fewer community-based services. Documentary analysis and professionals’ interviews suggested difficulties with early access to services, low suspicion index amongst some GPs and restricted referral routes. Interviews indicated lack of managed accommodation for difficult to treat patients, professional workforce shortages, a need for strategic leadership, nurse-led clinics and structured career paths for TB nurses and few social care/outreach workers to support patients with complex needs. Conclusions This paper has identified key issues relating to London’s TB services’ organisation, delivery, professional workforce and skill mix. The majority of these present challenges which need to be addressed as part of the future development of a strategic framework for a pan-London TB service. More consistent strategic planning/co-ordination and sharing of best practice is needed, together with a review of pan-London TB workforce development strategy, encompassing changing professional roles, skills development needs and patient pathways. These findings may be relevant with the development of TB services in other European cities. PMID:22805234

IMPACT OF CIGARETTE SMOKING ON RATES AND CLINICAL PROGNOSIS OF PULMONARY TUBERCULOSIS IN SOUTHERN MEXICO

PubMed Central

Bonacci, Robert A.; Cruz-Hervert, Luis Pablo; García-García, Lourdes; Reynales-Shigematsu, Luz Myriam; Ferreyra-Reyes, Leticia; Bobadilla-del-Valle, Miriam; Canizales-Quintero, Sergio; Ferreira-Guerrero, Elizabeth; Báez-Saldaña, Renata; Téllez-Vázquez, Norma; Mongua-Rodríguez, Norma; Montero-Campos, Rogelio; Delgado-Sánchez, Guadalupe; Martínez-Gamboa, Rosa Areli; Cano-Arellano, Bulmaro; Sifuentes-Osornio, José; de León, Alfredo Ponce

2012-01-01

Objectives To examine the relationship between cigarette smoking and incidence and mortality rates of pulmonary tuberculosis (TB) and treatment outcomes. Materials From 1995-2010, we analyzed data from 1062 patients with TB and from 2001-2004, 2951 contacts in Southern Mexico. Patients with acid-fast bacilli or Mycobacterium tuberculosis in sputum samples underwent epidemiological, clinical and mycobacteriological evaluation and received treatment by the local DOTS program. Results Consumers of 1-10 (LS) or 11 or more (HS) cigarettes per day incidence (1.75 and 11.79) and mortality (HS,17.74) smoker-nonsmoker rate ratios were significantly higher for smokers. Smoker population was more likely to experience unfavorable treatment outcomes (HS, adjusted OR 2.36) and retreatment (LS and HS, adjusted hazard ratio (HR) 2.14 and 2.37). Contacts that smoked had a higher probability of developing active TB (HR 2.38) during follow up. Conclusions Results indicate the need of incorporating smoking prevention and cessation, especially among men, into international TB control strategies. PMID:22982014

Photoluminescence of Alq3 - and Tb-activated aluminium-tris(8-hydroxyquinoline) complex for blue chip-excited OLEDs.

PubMed

Yawalkar, P W; Dhoble, S J; Thejo Kalyani, N; Atram, R G; Kokode, N S

2013-01-01

The tris(8-hydroxyquinoline)-aluminium complex is the most important and widely studied as electron transporting and green light emitting material. Alq(3) and Tb(x) Al((1-x)) q(3) have been synthesized (where x = 0.1, 0.3, 0.5, 0.7 and 0.9) and blended films of Alq(3) and Tb(x) Al((1-x)) q(3) with PMMA and PS at different percentage weight (wt%) concentrations (e.g., 0.1, 1, 5, 10, 25 and 50 wt%) have been prepared. The synthesized materials and their blended thin films have been characterized by a photoluminescence (PL) technique; the synthesis and PL characterization are reported in this paper. The synthesized metal complex shows bright emission of green light with blue light excitation (440 nm) and the prepared Tb(x) Al((1-x)) q(3) phosphor may be applicable in blue chip-excited OLEDs for the newly developed wallpaper lighting technology. Copyright © 2012 John Wiley & Sons, Ltd.

Isoniazid Preventive Therapy and Risk for Resistant Tuberculosis

PubMed Central

Balcells, Maria Elvira; Thomas, Sara L.; Godfrey-Faussett, Peter

2006-01-01

In the context of tuberculosis (TB) resurgence, isoniazid preventive therapy (IPT) is increasingly promoted, but concerns about the risk for development of isoniazid-resistant tuberculosis may hinder its widespread implementation. We conducted a systematic review of data published since 1951 to assess the effect of primary IPT on the risk for isoniazid-resistant TB. Different definitions of isoniazid resistance were used, which affected summary effect estimates; we report the most consistent results. When all 13 studies (N = 18,095 persons in isoniazid groups and N = 17,985 persons in control groups) were combined, the summary relative risk for resistance was 1.45 (95% confidence interval 0.85–2.47). Results were similar when studies of HIV-uninfected and HIV-infected persons were considered separately. Analyses were limited by small numbers and incomplete testing of isolates, but findings do not exclude an increased risk for isoniazid-resistant TB after IPT. The diagnosis of active TB should be excluded before IPT. Continued surveillance for isoniazid resistance is essential. PMID:16704830

The Progress of Therapeutic Vaccination with Regard to Tuberculosis.

PubMed

Cardona, Pere-Joan

2016-01-01

A major problem with tuberculosis (TB) control is the long duration of drug therapy-both for latent and for active TB. Therapeutic vaccination has been postulated to improve this situation, and to this end there are several candidates already in clinical phases of development. These candidates follow two main designs, namely bacilli-directed therapy based on inactivated -whole or -fragmented bacillus ( Mycobacterium w and RUTI) or fusion proteins that integrate non-replicating bacilli -related antigens (H56 vaccine), and host-directed therapy to reduce the tissue destruction. The administration of inactivated Mycobacterium vaccae prevents the "Koch phenomenon" response, and oral administration of heat-killed Mycobacterium manresensis prevents excessive neutrophilic infiltration of the lesions. This review also tries to explain the success of Mycobacterium tuberculosis by reviewing its evolution from infection to disease, and highlights the lack of a definitive understanding of the natural history of TB pathology and the need to improve our knowledge on TB immunology and pathogenesis.

The Progress of Therapeutic Vaccination with Regard to Tuberculosis

PubMed Central

Cardona, Pere-Joan

2016-01-01

A major problem with tuberculosis (TB) control is the long duration of drug therapy–both for latent and for active TB. Therapeutic vaccination has been postulated to improve this situation, and to this end there are several candidates already in clinical phases of development. These candidates follow two main designs, namely bacilli-directed therapy based on inactivated -whole or -fragmented bacillus (Mycobacterium w and RUTI) or fusion proteins that integrate non-replicating bacilli -related antigens (H56 vaccine), and host-directed therapy to reduce the tissue destruction. The administration of inactivated Mycobacterium vaccae prevents the “Koch phenomenon” response, and oral administration of heat-killed Mycobacterium manresensis prevents excessive neutrophilic infiltration of the lesions. This review also tries to explain the success of Mycobacterium tuberculosis by reviewing its evolution from infection to disease, and highlights the lack of a definitive understanding of the natural history of TB pathology and the need to improve our knowledge on TB immunology and pathogenesis. PMID:27733848

Serum bilirubin levels are inversely associated with PAI-1 and fibrinogen in Korean subjects.

PubMed

Cho, Hyun Sun; Lee, Sung Won; Kim, Eun Sook; Shin, Juyoung; Moon, Sung Dae; Han, Je Ho; Cha, Bong Yun

2016-01-01

Oxidative stress may contribute to atherosclerosis and increased activation of the coagulation pathway. Bilirubin may reduce activation of the hemostatic system to inhibit oxidative stress, which would explain its cardioprotective properties shown in many epidemiological studies. This study investigated the association of serum bilirubin with fibrinogen and plasminogen activator inhibitor-1 (PAI-1), respectively. A cross-sectional analysis was performed on 968 subjects (mean age, 56.0 ± 11.2 years; 61.1% men) undergoing a general health checkup. Serum biochemistry was analyzed including bilirubin subtypes, insulin resistance (using homeostasis model of assessment [HOMA]), C-reactive protein (CRP), fibrinogen, and PAI-1. Compared with subjects with a total bilirubin (TB) concentration of <10.0 μmol/L, those with a TB concentration of >17.1 μmol/L had a smaller waist circumference, a lower triglyceride level, a lower prevalence of metabolic syndrome, and decreased HOMA-IR and CRP levels. Correlation analysis revealed linear relationships of fibrinogen with TB and direct bilirubin (DB), whereas PAI-1 was correlated with DB. After adjustment for confounding factors, bilirubin levels were inversely associated with fibrinogen and PAI-1 levels, respectively. Multivariate regression models showed a negative linear relationship between all types of bilirubin and fibrinogen, whereas there was a significant linear relationship between PAI-1 and DB. High bilirubin concentrations were independently associated with low levels of fibrinogen and PAI-1, respectively. The association between TB and PAI-1 was confined to the highest TB concentration category whereas DB showed a linear association with PAI-1. Bilirubin may protect against the development of atherothrombosis by reducing the hemostatic response. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Hot-blooded singers: endothermy facilitates crepuscular signaling in African platypleurine cicadas (Hemiptera: Cicadidae: Platypleura spp.).

PubMed

Sanborn, Allen F; Villet, Martin H; Phillips, Polly K

2003-07-01

The cicada genus Platypleura has a wide distribution across Africa and southern Asia. We describe endothermic thermoregulation in four South African species that show crepuscular signaling behavior. This is the first evidence of thermoregulation in platypleurine cicadas. Field measurements of body temperature ( T(b)) show that these animals regulate T(b) through endogenous heat production. Maximum T(b) measured was 22.1 degrees C above ambient temperature during calling activity at dusk. The mean T(b) during dusk activity did not differ from the mean T(b) during diurnal activity. A unique behavior for cicadas, a temperature-dependent telescoping pulsation of the abdomen, was observed in the laboratory during endogenous warm-up. This behavior is part of a unique method of heat generation in endothermic cicadas. Males generally call from trunks and branches within the canopy and appear to use endothermy even when the sun is available to elevate T(b). Endothermy may provide the cicadas with the advantage of decreasing predation and acoustic competition by permitting calling from perches that most complement their cryptic coloration patterns and that ectotherms cannot use due to thermal constraints. In addition, endothermy may permit calling activity during crepuscular hours when atmospheric conditions are optimal for acoustic communication and predation risks are minimal.

Immune modulation properties of herbal plant leaves: Phyllanthus niruri aqueous extract on immune cells of tuberculosis patient - in vitro study.

PubMed

Putri, Denise Utami; Rintiswati, Ning; Soesatyo, Marsetyawan Hne; Haryana, Sofia Mubarika

2018-02-01

Disease progression in Tuberculosis (TB) is dependent on host's immune system. Phyllanthus niruri, a traditional herb, has long been used to boost immune system in Indonesian society. This study aimed to observe the potential role of P. niruri in inducing immune cells activity in TB patients by in vitro approach. Peripheral blood mononuclear cells (PBMCs) and macrophages were collected from active pulmonary TB patients. After stimulation with graded doses of P. niruri aqueous extract, cell proliferation, phagocytic activity and nitric oxide (NO) release were analysed. P. niruri aqueous extract induced proliferation of PBMCs, increased NO release, and improved macrophages phagocytic activity. These effects were observed in a dose-dependent manner. This may lead to further research for the potential role of P. niruri as immunomodulatory adjuvant therapy for TB patients.

Use of Activity Space in a Tuberculosis Outbreak: Bringing Homeless Persons Into Spatial Analyses.

PubMed

Worrell, Mary Claire; Kramer, Michael; Yamin, Aliya; Ray, Susan M; Goswami, Neela D

2017-01-01

Tuberculosis (TB) causes significant morbidity and mortality in US cities, particularly in poor, transient populations. During a TB outbreak in Fulton County, Atlanta, GA, we aimed to determine whether local maps created from multiple locations of personal activity per case would differ significantly from traditional maps created from single residential address. Data were abstracted for patients with TB disease diagnosed in 2008-2014 and receiving care at the Fulton County Health Department. Clinical and activity location data were abstracted from charts. Kernel density methods, activity space analysis, and overlay with homeless shelter locations were used to characterize case spatial distribution when using single versus multiple addresses. Data were collected for 198 TB cases, with over 30% homeless US-born cases included. Greater spatial dispersion of cases was found when utilizing multiple versus single addresses per case. Activity spaces of homeless and isoniazid (INH)-resistant cases were more spatially congruent with one another than non-homeless and INH-susceptible cases ( P < .0001 and P < .0001, respectively). Innovative spatial methods allowed us to more comprehensively capture the geography of TB-infected homeless persons, who made up a large portion of the Fulton County outbreak. We demonstrate how activity space analysis, prominent in exposure science and chronic disease, supports that routine capture of multiple location TB data may facilitate spatially different public health interventions than traditional surveillance maps. © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Next-Generation Vaccines Based on Bacille Calmette–Guérin

PubMed Central

Nieuwenhuizen, Natalie E.; Kaufmann, Stefan H. E.

2018-01-01

Tuberculosis (TB), caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb), remains a major health threat. A live, attenuated mycobacterium known as Bacille Calmette–Guérin (BCG), derived from the causative agent of cattle TB, Mycobacterium bovis, has been in clinical use as a vaccine for 90 years. The current incidence of TB demonstrates that BCG fails to protect sufficiently against pulmonary TB, the major disease manifestation and source of dissemination. The protective efficacy of BCG is on average 50% but varies substantially with geographical location and is poorer in those with previous exposure to mycobacteria. BCG can also cause adverse reactions in immunocompromised individuals. However, BCG has contributed to reduced infant TB mortality by protecting against extrapulmonary TB. In addition, BCG has been associated with reduced general childhood mortality by stimulating immune responses. In order to improve the efficacy of BCG, two major strategies have been employed. The first involves the development of recombinant live mycobacterial vaccines with improved efficacy and safety. The second strategy is to boost BCG with subunit vaccines containing Mtb antigens. This article reviews recombinant BCG strains that have been tested against TB in animal models. This includes BCG strains that have been engineered to induce increased immune responses by the insertion of genes for Mtb antigens, mammalian cytokines, or host resistance factors, the insertion of bacterial toxin-derived adjuvants, and the manipulation of bacterial genes in order to increase antigen presentation and immune activation. Subunit vaccines for boosting BCG are also briefly discussed. PMID:29459859

Molecular Epidemiology of Pulmonary Tuberculosis in Belgrade, Central Serbia

PubMed Central

Vuković, Dragana; Rüsch-Gerdes, Sabine; Savić, Branislava; Niemann, Stefan

2003-01-01

In order to gain precise data on the actual epidemiology of tuberculosis (TB) in Belgrade, central Serbia, we conducted the molecular epidemiological investigation described herein. IS6110 restriction fragment length polymorphism (RFLP) typing of 176 Mycobacterium tuberculosis isolates was performed. These strains were obtained from 48.4% of all patients diagnosed with culture-proven pulmonary TB from April through September 1998 and from May through October 1999. Clusters containing strains with identical RFLP IS6110 patterns were assumed to have arisen from recent transmission. Of the 176 cases, 55 (31.2%) were grouped into 23 clusters ranging in size from two to six patients. Nearly 80% of clustered patients were directly interviewed, and transmission between family-unrelated contacts was found to be predominant in the study population. Classical contact investigation identified only 2 (3.6%) of the 55 clustered patients. The clustering of TB patients was not associated with any demographic or clinical characteristic other than infection with multidrug-resistant (MDR) M. tuberculosis strains. Nearly 70% of MDR strains were clustered, which indicates active transmission of MDR TB in Belgrade. However, this was not observed by conventional epidemiologic surveillance. In conclusion, the first molecular epidemiologic analysis of TB in the region revealed frequent recent transmission of TB and pointed out significant shortcomings of the current concept for conventional contact tracing. The results presented also demonstrate that transmission of MDR TB in Belgrade is not optimally controlled, and they provide support for the development of improved control strategies, including application of molecular methods. PMID:12958271

Recent advances in tuberculosis diagnostics in resource-limited settings.

PubMed

Seki, Mitsuko; Kim, Chang-Ki; Hayakawa, Satoshi; Mitarai, Satoshi

2018-04-19

Smear-negative and drug-resistant cases of tuberculosis (TB) disease necessitate the development of new diagnostic methods, especially in resource-limited settings. To improve the current TB situations, sensitive and specific TB point-of-care tests (POCTs) should be developed. This review addresses the current status of TB, novel diagnostic methodologies for TB, and the impact of those new diagnostics on TB control in such situations. Moreover, the perspective of TB management based on laboratory examinations is described. Smear microscopy with sputum samples is the only laboratory examination available in many resource-limited settings and is still used globally. Several nucleic acid amplification tests (NATs) have been developed. The World Health Organization (WHO) endorsed novel diagnostics based on NATs and updated their definition of a bacteriologically confirmed case requiring the biological specimen to be positive by smear microscopy, culture, or the WHO-recommended rapid diagnostic protocols. The use of new diagnostics increased the number of bacteriologically confirmed TB cases. Novel diagnostics are now available, but their sensitivity is still lower than that of conventional liquid culture method. To address the increasing incidence of TB, more resources including novel diagnostics as POCTs with higher sensitivity must be allocated to healthcare systems.

Combination of gene expression patterns in whole blood discriminate between tuberculosis infection states

PubMed Central

2014-01-01

Background Genetic factors are involved in susceptibility or protection to tuberculosis (TB). Apart from gene polymorphisms and mutations, changes in levels of gene expression, induced by non-genetic factors, may also determine whether individuals progress to active TB. Methods We analysed the expression level of 45 genes in a total of 47 individuals (23 healthy household contacts and 24 new smear-positive pulmonary TB patients) in Addis Ababa using a dual colour multiplex ligation-dependent probe amplification (dcRT-MLPA) technique to assess gene expression profiles that may be used to distinguish TB cases and their contacts and also latently infected (LTBI) and uninfected household contacts. Results The gene expression level of BLR1, Bcl2, IL4d2, IL7R, FCGR1A, MARCO, MMP9, CCL19, and LTF had significant discriminatory power between sputum smear-positive TB cases and household contacts, with AUCs of 0.84, 0.81, 0.79, 0.79, 0.78, 0.76, 0.75, 0.75 and 0.68 respectively. The combination of Bcl2, BLR1, FCGR1A, IL4d2 and MARCO identified 91.66% of active TB cases and 95.65% of household contacts without active TB. The expression of CCL19, TGFB1, and Foxp3 showed significant difference between LTBI and uninfected contacts, with AUCs of 0.85, 0.82, and 0.75, respectively, whereas the combination of BPI, CCL19, FoxP3, FPR1 and TGFB1 identified 90.9% of QFT- and 91.6% of QFT+ household contacts. Conclusions Expression of single and especially combinations of host genes can accurately differentiate between active TB cases and healthy individuals as well as between LTBI and uninfected contacts. PMID:24885723

Evaluation of the performance of two tuberculosis interferon gamma release assays (IGRA-ELISA and T-SPOT.TB) for diagnosing Mycobacterium tuberculosis infection.

PubMed

Wang, Linchuan; Tian, Xu-Dong; Yu, Yan; Chen, Wei

2018-04-01

The IGRA-ELISA and T-SPOT.TB are widely used in China. The aim of the study was to evaluate the performance of the two assays in diagnosis Mycobacterium tuberculosis infection. Of the 3727 patients in the study, 204 underwent testing using both the T-SPOT.TB and IGRA-ELISA, 1794 were tested using the T-SPOT.TB only, and 1729 were tested using the IGRA-ELISA only. The positive rate and consistency of the two assays were analyzed, and their sensitivity and specificity for diagnosing active tuberculosis were compared. There were no significant differences in the positive rate between the T-SPOT.TB test (25.8%) and IGRA-ELISA (28.6%), p = .065. The two assays were highly consistent, with a kappa value of 0.852 (p < .0001) and a total coincidence rate of 92.7%. For the diagnosis of active tuberculosis, the sensitivity and specificity values of the T-SPOT.TB test were 82.9% (107/129) and 78.6% (1309/1665), respectively, and those of IGRA-ELISA were 81.7% (94/115) and 75.2% (1214/1614), respectively. There were no significant differences in sensitivity (p > .05), but the specificity of the T-SPOT.TB test was slightly higher than that of IGRA-ELISA (p = .023). Both in terms of diagnosing M. tuberculosis infection and ruling out active tuberculosis, the performance of the IGRA-ELISA-a simple, almost labor-free assay that allows simultaneous processing of a very large number of samples-was well-matched with that of T-SPOT.TB test. However, IGRAs cannot be used as the only test to diagnose active tuberculosis. Copyright © 2018 Elsevier B.V. All rights reserved.

Migrants and tuberculosis: analysing epidemiological data with ethnography.

PubMed

Littleton, Judith; Park, Julie; Thornley, Craig; Anderson, Anneka; Lawrence, Jody

2008-04-01

Media portrayals of tuberculosis (TB) in New Zealand are of immigrants who enter the country with active disease and pose a threat to inhabitants, which fosters a popular perception that border control is the best and only response to disease control. This paper reviews both New Zealand and international data on TB rates, causes and transmission among migrant populations to elucidate the precise nature of the link between immigration and TB rates. Recent information from scholarly journals on immigration and TB was reviewed. Surveillance data from New Zealand and comparable information from other low-incidence countries were reviewed. The importation of active TB is only a minor part of the total TB burden. While effective border control is essential, equally, if not more important, are the circumstances that promote the reactivation of latent TB infection in migrant communities, including migrants' experiences in transit and after arrival, structural conditions, and personal characteristics. For sound prevention strategies, attention needs to be paid to the existence of transnational communities and the conditions for migrants, rather than placing a singular focus on place of birth.

[Outbreaks of tuberculosis in facilities used by an unspecified number of people near a train station - problems regarding tuberculosis in urban areas ].

PubMed

Kinoshita, Setsuko; Ohmori, Masako; Tsukamoto, Kazuhide; Ohtsuka, Goro; Mashiko, Mari; Fujiu, Michiko; Takahashi, Tsukasa; Hoshino, Hitoshi

2007-10-01

To report on the mass outbreak of tuberculosis (TB) in an urban area and to discuss current issues regarding the problem of TB in the metropolis. Case studies were mainly carried out. Discussions on the route of infection are based on the results of DNA fingerprinting analysis for M. tuberculosis and on information obtained by epidemiological research. In an approximately 500-meter vicinity around Kawasaki Station in Kawasaki City, nine incidences of people contracting TB were reported during the period of one year and five months starting February 2005. Seven of the nine patients were resistant for streptomycin, and the tubercle bacilli of five patients showed identical patterns based on DNA fingerprinting analysis. These nine patients were relatively young, ranging from 16 years to 55 years in age, and three of the patients were homeless. The area for daily activities for all nine patients is a neighborhood of Kawasaki Station. Based on results from an epidemiologic survey, it is suspected that nine patients had come into contact with each other TB patient in places such as "Net cafes" before they developed TB. Based on the epidemiological and bacteriological results, the route of infection related to this series of TB outbreak is considered to be facilities used by an unspecified number of people such as "Net cafes." Such "Net cafes" are open 24 hours a day and are used by an unspecified number of people, who go to such places to Internet or enjoy comic books. Recently, there are many "Net cafes" in the city, and has become to be used as temporary places to sleep, not only by young people but also by socially vulnerable people, such as the homeless. This study suggests that infection can happen easily once someone begins to discharge TB bacilli in such environments, due to young people, who for the most part are not infected with TB bacilli, and high-risk people, who have higher probability of developing the disease, sharing a closed space for a long period of time. Such social environments may also affect the distribution of TB to lean towards urban areas. The TB control program in the metropolis should be planned and carried out giving consideration to social aspects.

Optimal treatment interruptions control of TB transmission model

NASA Astrophysics Data System (ADS)

Nainggolan, Jonner; Suparwati, Titik; Kawuwung, Westy B.

2018-03-01

A tuberculosis model which incorporates treatment interruptions of infectives is established. Optimal control of individuals infected with active TB is given in the model. It is obtained that the control reproduction numbers is smaller than the reproduction number, this means treatment controls could optimize the decrease in the spread of active TB. For this model, controls on treatment of infection individuals to reduce the actively infected individual populations, by application the Pontryagins Maximum Principle for optimal control. The result further emphasized the importance of controlling disease relapse in reducing the number of actively infected and treatment interruptions individuals with tuberculosis.

Universal post-arrival screening for child refugees in Australia: isn't it time?

PubMed

Patradoon-Ho, Patrick S; Ambler, Rosemary W

2012-02-01

It is known that the refugee population in Australia is at risk of tuberculosis (TB) and children with TB infection can develop active disease with devastating consequence. Currently, in New South Wales (NSW) and possibly other Australian States and Territories, there are different and complex health-screening pathways for newly arrived refugees. This is compounded by various factors, such as social and language difficulties for refugees to access healthcare and limited pre-embarkation screening. In this Viewpoint article, we present a child refugee in Australia with TB and use this case to reason why a universal post-arrival health screening programme should be established. © 2010 The Authors. Journal of Paediatrics and Child Health © 2010 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Innovative combination of electrolysis and Fe(II)-activated persulfate oxidation for improving the dewaterability of waste activated sludge.

PubMed

Zhen, Guang-Yin; Lu, Xue-Qin; Li, Yu-You; Zhao, You-Cai

2013-05-01

The feasibility of electrolysis integrated with Fe(II)-activated persulfate (S2O8(2-)) oxidation to improve waste activated sludge (WAS) dewaterability was evaluated. The physicochemical properties (sludge volume (SV), total suspended solids (TSS) and volatile suspended solids (VSS)) and extracellular polymeric substances (EPS), including slime EPS, loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS) were characterized to identify their exact roles in sludge dewatering. While dewaterability negatively corresponded to LB-EPS, TB-EPS, protein (PN) and polysaccharide (PS) in LB-EPS and TB-EPS, it was independent of SV, TSS, VSS, slime EPS and PN/PS. Further study through scanning electron microscope (SEM) verified the entrapment of bacterial cells by TB-EPS, protecting them against electrolysis disruption. Comparatively, electrolysis integrated with S2O8(2-)/Fe(II) oxidation was able to effectively disrupt the protective barrier and crack the entrapped cells, releasing the water inside EPS and cells. Therefore, the destruction of both TB-EPS and cells is the fundamental reason for the enhanced dewaterability. Copyright © 2013 Elsevier Ltd. All rights reserved.

Layered rare-earth hydroxide and oxide nanoplates of the Y/Tb/Eu system: phase-controlled processing, structure characterization and color-tunable photoluminescence via selective excitation and efficient energy transfer.

PubMed

Wu, Xiaoli; Li, Ji-Guang; Li, Jinkai; Zhu, Qi; Li, Xiaodong; Sun, Xudong; Sakka, Yoshio

2013-02-01

Well-crystallized (Y 0.97- x Tb 0.03 Eu x ) 2 (OH) 5 NO 3 · n H 2 O ( x = 0-0.03) layered rare-earth hydroxide (LRH) nanoflakes of a pure high-hydration phase have been produced by autoclaving from the nitrate/NH 4 OH reaction system under the optimized conditions of 100 °C and pH ∼7.0. The flakes were then converted into (Y 0.97- x Tb 0.03 Eu x ) 2 O 3 phosphor nanoplates with color-tunable photoluminescence. Detailed structural characterizations confirmed that LRH solid solutions contained NO 3 - anions intercalated between the layers. Characteristic Tb 3+ and Eu 3+ emissions were detected in the ternary LRHs by selectively exciting the two types of activators, and the energy transfer from Tb 3+ to Eu 3+ was observed. Annealing the LRHs at 1100 °C produced cubic-lattice (Y 0.97- x Tb 0.03 Eu x ) 2 O 3 solid-solution nanoplates with exposed 222 facets. Multicolor, intensity-adjustable luminescence was attained by varying the excitation wavelength from ∼249 nm (the charge transfer excitation band of Eu 3+ ) to 278 nm (the 4f 8 -4f 7 5d 1 transition of Tb 3+ ). Unitizing the efficient Tb 3+ to Eu 3+ energy transfer, the emission color of (Y 0.97- x Tb 0.03 Eu x ) 2 O 3 was tuned from approximately green to yellowish-orange by varying the Eu 3+ /Tb 3+ ratio. At the optimal Eu 3+ content of x = 0.01, the efficiency of energy transfer was ∼91% and the transfer mechanism was suggested to be electric multipole interactions. The phosphor nanoplates developed in this work may be incorporated in luminescent films and find various lighting and display applications.

Photoluminescence properties of phosphors based on Lu3+-stabilized Gd3Al5O12:Tb3+/Ce3+ garnet solid solutions

NASA Astrophysics Data System (ADS)

Li, Jinkai; Li, Ji-Guang; Li, Xiaodong; Sun, Xudong

2016-12-01

The Gd3Al5O12:Tb/Ce (GdAG:Tb/Ce) garnet solutions effectively stabilized by Lu3+ have been achieved by calcining their precursor at 1300 °C. Detailed characterizations are given to the materials in terms of XRD, FE-SEM, BET, PL/PLE, and fluorescence decay analysis. The occurrence of Gd3+ and Tb3+ transitions from the photoluminescence excitation spectrum monitoring the Ce3+ yellow emission strongly confirmed the efficient Gd3+ → Ce3+ and Tb3+ → Ce3+ energy transfer. The [(Gd0.8Lu0.2)0.99-xCe0.01Tbx]AG (x = 0-0.1) phosphors with good dispersion and uniform particle size exhibit various luminescent properties under different excitation wavelength of 275, 338, and 457 nm, respectively. The photoluminescence comparison indicated that owing to the Gd3+ → Ce3+ and Tb3+ → Ce3+ energy transfer, the best luminescent phosphor [(Gd0.8Lu0.2)0.89Ce0.01 Tb0.1]AG is almost identical to the well-known YAG:Ce, higher than LuAG:Ce in emission intensity, and has a substantially red-shifted emission band that is desired for warm-white lighting. The Tb3+ → Ce3+ energy transfer was suggested to be electric multipolar interactions, and the processes of energy migration among the optically active Gd3+, Tb3+, and Ce3+ ions were discussed in detail. Fluorescence decay analysis found the lifetime for the Ce3+ emission hardly changes with the Tb3+ incorporation. The [(Gd0.8Lu0.2)0.99-xCe0.01Tbx]AG garnets developed in this work may serve as a new type of phosphor that hopefully meets the requirements of various lighting, optical display, and scintillation applications.

Utilizing Machine Learning to Downscale SMAP L3_SM_P Brightness Temperatures in Iowa for Agricultural Applications

NASA Astrophysics Data System (ADS)

Chakrabarti, S.; Judge, J.; Bindlish, R.; Bongiovanni, T.; Jackson, T. J.

2016-12-01

The NASA Soil Moisture Active Passive (SMAP) mission provides global observations of brightness temperatures (TB) at 36km. For these observations to be relevant to studies in agricultural regions, the TB values need to be downscaled to finer resolutions. In this study, a machine learning algorithm is introduced for downscaling of TB from 36km to 9km. The algorithm uses image segmentation to cluster the study region based on meteorological and land cover similarity, followed by a support vector machine based regression that computes the value of the disaggregated TB at all pixels. High resolution remote sensing products such as land surface temperature, normalized difference vegetation index, enhanced vegetation index, precipitation, soil texture, and land-cover were used for downscaling. The algorithm was implemented in Iowa, United States, during the growing season from April to July 2015 when the SMAP L3-SM_AP TB product at 9 km was available for comparison. In addition, the downscaled estimates from the algorithm are compared with 9km TB obtained by resampling SMAP L1B_TB product at 36km. It was found that the downscaled TB were very similar to the SMAP-L3_SM _AP TB product, even for vegetated areas with a mean difference ≤ 5K. However, the standard deviation of the downscaled was lower by 7K than that of the AP product. The probability density functions of the downscaled TB were similar to the SMAP- TB. The results indicate that these downscaling algorithms may be used for downscaling TB using complex non-linear correlations on a grid without using active microwave observations.

Second generation multiple reaction monitoring assays for enhanced detection of ultra-low abundance Mycobacterium tuberculosis peptides in human serum.

PubMed

Mehaffy, Carolina; Dobos, Karen M; Nahid, Payam; Kruh-Garcia, Nicole A

2017-01-01

Mycobacterium tuberculosis (Mtb) is the causative agent of Tuberculosis (TB), the number one cause of death due to an infectious disease. TB diagnosis is performed by microscopy, culture or PCR amplification of bacterial DNA, all of which require patient sputum or the biopsy of infected tissue. Detection of mycobacterial products in serum, as biomarkers of diagnosis or disease status would provide an improvement over current methods. Due to the low-abundance of mycobacterial products in serum, we have explored exosome enrichment to improve sensitivity. Mtb resides intracellularly where its secreted proteins have been shown to be packaged into host exosomes and released into the bloodstream. Exosomes can be readily purified assuring an enrichment of mycobacterial analytes from the complex mix of host serum proteins. Multiple reaction monitoring assays were optimized for the enhanced detection of 41 Mtb peptides in exosomes purified from the serum of individuals with TB. Exosomes isolated from the serum of healthy individuals was used to create and validate a unique data analysis algorithm and identify filters to reduce the rate of false positives, attributed to host m / z interference. The final optimized method was tested in 40 exosome samples from TB positive patients. Our enhanced methods provide limit of detection and quantification averaging in the low femtomolar range for detection of mycobacterial products in serum. At least one mycobacterial peptide was identified in 92.5% of the TB positive patients. Four peptides from the Mtb proteins, Cfp2, Mpt32, Mpt64 and BfrB, show normalized total peak areas significantly higher in individuals with active TB as compared to healthy controls; three of the peptides from these proteins have not previously been associated with serum exosomes from individuals with active TB disease. Some of the detected peptides were significantly associated with specific geographical locations, highlighting potential markers that can be linked to the Mtb strains circulating within each given region. An enhanced MRM method to detect ultra-low abundance Mtb peptides in human serum exosomes is demonstrated, highlighting the potential of this methodology for TB diagnostic biomarker development.

Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy.

PubMed

Honeyborne, Isobella; McHugh, Timothy D; Kuittinen, Iitu; Cichonska, Anna; Evangelopoulos, Dimitrios; Ronacher, Katharina; van Helden, Paul D; Gillespie, Stephen H; Fernandez-Reyes, Delmiro; Walzl, Gerhard; Rousu, Juho; Butcher, Philip D; Waddell, Simon J

2016-04-07

New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb mRNA profiles 0-2 weeks into chemotherapy predict the efficacy of treatment 6 weeks later. These observations advocate assaying dynamic bacterial phenotypes through drug therapy as biomarkers for treatment success.

How much is tuberculosis screening worth? Estimating the value of active case finding for tuberculosis in South Africa, China, and India.

PubMed

Azman, Andrew S; Golub, Jonathan E; Dowdy, David W

2014-10-30

Current approaches are unlikely to achieve the aggressive global tuberculosis (TB) control targets set for 2035 and beyond. Active case finding (ACF) may be an important tool for augmenting existing strategies, but the cost-effectiveness of ACF remains uncertain. Program evaluators can often measure the cost of ACF per TB case detected, but how this accessible measure translates into traditional metrics of cost-effectiveness, such as the cost per disability-adjusted life year (DALY), remains unclear. We constructed dynamic models of TB in India, China, and South Africa to explore the medium-term impact and cost-effectiveness of generic ACF activities, conceptualized separately as discrete (2-year) campaigns and as continuous activities integrated into ongoing TB control programs. Our primary outcome was the cost per DALY, measured in relationship to the cost per TB case actively detected and started on treatment. Discrete campaigns costing up to $1,200 (95% uncertainty range [UR] 850-2,043) per case actively detected and started on treatment in India, $3,800 (95% UR 2,706-6,392) in China, and $9,400 (95% UR 6,957-13,221) in South Africa were all highly cost-effective (cost per DALY averted less than per capita gross domestic product). Prolonged integration was even more effective and cost-effective. Short-term assessments of ACF dramatically underestimated potential longer term gains; for example, an assessment of an ACF program at 2 years might find a non-significant 11% reduction in prevalence, but a 10-year evaluation of that same intervention would show a 33% reduction. ACF can be a powerful and highly cost-effective tool in the fight against TB. Given that short-term assessments may dramatically underestimate medium-term effectiveness, current willingness to pay may be too low. ACF should receive strong consideration as a basic tool for TB control in most high-burden settings, even when it may cost over $1,000 to detect and initiate treatment for each extra case of active TB.

Potential Immunological Biomarkers for Detection of Mycobacterium tuberculosis Infection in a Setting Where M. tuberculosis Is Endemic, Ethiopia.

PubMed

Teklu, Takele; Kwon, Keehwan; Wondale, Biniam; HaileMariam, Milkessa; Zewude, Aboma; Medhin, Girmay; Legesse, Mengistu; Pieper, Rembert; Ameni, Gobena

2018-04-01

Accurate diagnosis and early treatment of tuberculosis (TB) and latent TB infection (LTBI) are vital to prevent and control TB. The lack of specific biomarkers hinders these efforts. This study's purpose was to screen immunological markers that discriminate Mycobacterium tuberculosis infection outcomes in a setting where it is endemic, Ethiopia. Whole blood from 90 participants was stimulated using the ESAT-6/CFP-10 antigen cocktail. The interferon gamma (IFN-γ)-based QuantiFERON diagnostic test was used to distinguish between LTBI and uninfected control cases. Forty cytokines/chemokines were detected from antigen-stimulated plasma supernatants (SPSs) and unstimulated plasma samples (UPSs) using human cytokine/chemokine antibody microarrays. Statistical tests allowed us to identify potential biomarkers that distinguish the TB, LTBI, and healthy control groups. As expected, the levels of IFN-γ in SPSs returned a high area under the receiver operating characteristic curve (AUC) value comparing healthy controls and LTBI cases (Z = 0.911; P < 0.001). The SPS data also indicated that interleukin 17 (IL-17) abundance discriminates LTBI from healthy controls (Z = 0.763; P = 0.001). RANTES and MIP-1β were significantly elevated in SPSs of TB-infected compared to healthy controls ( P < 0.05), while IL-12p40 and soluble tumor necrosis factor receptor II (sTNF-RII) were significantly increased in active TB cases compared to the combined LTBI and control groups ( P < 0.05). Interestingly, quantitative changes for RANTES were observed using both SPSs and UPSs, with P values of 0.013 and 0.012, respectively, in active TB versus LTBI cases and 0.001 and 0.002, respectively, in active TB versus healthy controls. These results encourage biomarker verification studies for IL-17 and RANTES. Combinations of these cytokines may complement IFN-γ measurements to diagnose LTBI and distinguish active TB from LTBI cases. Copyright © 2018 American Society for Microbiology.

Achievements in and Challenges of Tuberculosis Control in South Korea.

PubMed

Kim, Ji Han; Yim, Jae-Joon

2015-11-01

After the Korean War (1950-1953), nearly 6.5% of South Korea's population had active tuberculosis (TB). In response, South Korea implemented the National Tuberculosis Program in 1962. From 1965 to 1995, the prevalence of bacteriologically confirmed pulmonary TB in South Korea decreased from 940 to 219 cases per 100,000 population. Astounding economic growth might have contributed to this result; however, TB incidence in South Korea remains the highest among high-income countries. The rate of decrease in TB incidence seems to have slowed over the past 15 years. A demographic shift toward an older population, many of whom have latent TB and various concurrent conditions, is challenging TB control efforts in South Korea. The increasing number of immigrants also plays a part in the prolonged battle against TB. A historical review of TB in South Korea provides an opportunity to understand national TB control efforts that are applicable to other parts of the world.

Ex-vivo characterization of regulatory T cells in pulmonary tuberculosis patients, latently infected persons, and healthy endemic controls.

PubMed

Zewdie, Martha; Howe, Rawleigh; Hoff, Søren T; Doherty, T Mark; Getachew, Nahom; Tarekegne, Azeb; Tessema, Bamlak; Yamuah, Lawrence; Aseffa, Abraham; Abebe, Markos

2016-09-01

Regulatory T cells (Treg) are an essential arm of adaptive immunity not only in tolerance and autoimmunity but also in infectious diseases. In Tuberculosis (TB), it has been suggested that the frequency of Tregs is higher in the blood of TB patients when compared to healthy controls with subsequent decline after treatment. However, with the discovery that FOXP3, the hallmark marker of Tregs, is not exclusive to Tregs and the lack of specific markers for Tregs, it has been a challenge to fully understand the role of Tregs in TB. We isolated PBMC from smear positive TB patients (TB, N = 13) before and after treatment, latent TB infected participants (LTBI, N = 8), and healthy endemic controls (EC, N = 9) and evaluated the frequency of different populations of Tregs and expression of FOXP3 by flowcytometry using six markers. The findings in this study showed that the association of Treg frequency with TB disease depends on the phenotypic markers used. While the frequency of CD4(+)CD25(+/hi) T cells was higher in TB patients compared to LTBI individuals, there was no difference in the frequency of CD4(+)CD25(+)FOXP3(+)CD127(lo) Treg among TB, LTBI, or EC. However, delineation of Tregs into active and naïve subsets revealed a significant increase in FOXP3 expression in active primed Tregs (CD4(+)CD25(+)FOXP3(+)CD127(lo)CD45RO(+)Ki-67(+)) of TB patients compared to LTBI and EC; and a significantly higher frequency of resting primed (CD45RO(+)Ki-67(-)) Treg in QuantiFERON negative EC compared to TB patients. After treatment completion, there was a significant decline in the frequency of active primed Treg, median (IQR) from 12.4% (9.5-21.9) of Tregs to 9.3% (7.0-12.2); P = 0.003 Wilcoxon signed rank test. We conclude that Treg subsets may be differentially regulated and expressed in TB disease, cure, and infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ex-vivo characterization of regulatory T cells in pulmonary tuberculosis patients, latently infected persons, and healthy endemic controls

PubMed Central

Zewdie, Martha; Howe, Rawleigh; Hoff, Søren T.; Doherty, T. Mark; Getachew, Nahom; Tarekegne, Azeb; Tessema, Bamlak; Yamuah, Lawrence; Aseffa, Abraham; Abebe, Markos

2016-01-01

SUMMARY Background Regulatory T cells (Treg) are an essential arm of adaptive immunity not only in tolerance and autoimmunity but also in infectious diseases. In Tuberculosis (TB), it has been suggested that the frequency of Tregs is higher in the blood of TB patients when compared to healthy controls with subsequent decline after treatment. However, with the discovery that FOXP3, the hallmark marker of Tregs, is not exclusive to Tregs and the lack of specific markers for Tregs, it has been a challenge to fully understand the role of Tregs in TB. Method We isolated PBMC from smear positive TB patients (TB, N = 13) before and after treatment, latent TB infected participants (LTBI, N = 8), and healthy endemic controls (EC, N = 9) and evaluated the frequency of different populations of Tregs and expression of FOXP3 by flowcytometry using six markers. Results The findings in this study showed that the association of Treg frequency with TB disease depends on the phenotypic markers used. While the frequency of CD4+CD25+/hi T cells was higher in TB patients compared to LTBI individuals, there was no difference in the frequency of CD4+CD25+FOXP3+CD127lo Treg among TB, LTBI, or EC. However, delineation of Tregs into active and naïve subsets revealed a significant increase in FOXP3 expression in active primed Tregs (CD4+CD25+FOXP3+CD127loCD45RO+Ki-67+) of TB patients compared to LTBI and EC; and a significantly higher frequency of resting primed (CD45RO+Ki-67−) Treg in QuantiFERON negative EC compared to TB patients. After treatment completion, there was a significant decline in the frequency of active primed Treg, median (IQR) from 12.4% (9.5–21.9) of Tregs to 9.3% (7.0–12.2); P = 0.003 Wilcoxon signed rank test. We conclude that Treg subsets may be differentially regulated and expressed in TB disease, cure, and infection. PMID:27553411

The Role of Apoptosis Associated Markers in Pathogenesis of Pulmonary Tuberculosis

ClinicalTrials.gov

2012-08-28

To Compare the Serum Apoptosis-associated Markers Between Patients With Active TB and Patients With LTBI; To Evaluate the Efficiency of Apoptosis-associated Markers to Differentiate Potential of Active TB From LTBI

The SCP2-thiolase-like protein (SLP) of Trypanosoma brucei is an enzyme involved in lipid metabolism.

PubMed

Harijan, Rajesh K; Mazet, Muriel; Kiema, Tiila R; Bouyssou, Guillaume; Alexson, Stefan E H; Bergmann, Ulrich; Moreau, Patrick; Michels, Paul A M; Bringaud, Frédéric; Wierenga, Rik K

2016-08-01

Bioinformatics studies have shown that the genomes of trypanosomatid species each encode one SCP2-thiolase-like protein (SLP), which is characterized by having the YDCF thiolase sequence fingerprint of the Cβ2-Cα2 loop. SLPs are only encoded by the genomes of these parasitic protists and not by those of mammals, including human. Deletion of the Trypanosoma brucei SLP gene (TbSLP) increases the doubling time of procyclic T. brucei and causes a 5-fold reduction of de novo sterol biosynthesis from glucose- and acetate-derived acetyl-CoA. Fluorescence analyses of EGFP-tagged TbSLP expressed in the parasite located the TbSLP in the mitochondrion. The crystal structure of TbSLP (refined at 1.75 Å resolution) confirms that TbSLP has the canonical dimeric thiolase fold. In addition, the structures of the TbSLP-acetoacetyl-CoA (1.90 Å) and TbSLP-malonyl-CoA (2.30 Å) complexes reveal that the two oxyanion holes of the thiolase active site are preserved. TbSLP binds malonyl-CoA tightly (Kd 90 µM), acetoacetyl-CoA moderately (Kd 0.9 mM) and acetyl-CoA and CoA very weakly. TbSLP possesses low malonyl-CoA decarboxylase activity. Altogether, the data show that TbSLP is a mitochondrial enzyme involved in lipid metabolism. Proteins 2016; 84:1075-1096. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A panel of Trypanosoma brucei strains tagged with blue and red-shifted luciferases for bioluminescent imaging in murine infection models.

PubMed

Van Reet, Nick; Van de Vyver, Hélène; Pyana, Patient Pati; Van der Linden, Anne Marie; Büscher, Philippe

2014-08-01

Genetic engineering with luciferase reporter genes allows monitoring Trypanosoma brucei (T.b.) infections in mice by in vivo bioluminescence imaging (BLI). Until recently, luminescent T.b. models were based on Renilla luciferase (RLuc) activity. Our study aimed at evaluating red-shifted luciferases for in vivo BLI in a set of diverse T.b. strains of all three subspecies, including some recently isolated from human patients. We transfected T.b. brucei, T.b. rhodesiense and T.b. gambiense strains with either RLuc, click beetle red (CBR) or Photinus pyralis RE9 (PpyRE9) luciferase and characterised their in vitro luciferase activity, growth profile and drug sensitivity, and their potential for in vivo BLI. Compared to RLuc, the red-shifted luciferases, CBR and PpyRE9, allow tracking of T.b. brucei AnTaR 1 trypanosomes with higher details on tissue distribution, and PpyRE9 allows detection of the parasites with a sensitivity of at least one order of magnitude higher than CBR luciferase. With CBR-tagged T.b. gambiense LiTaR1, T.b. rhodesiense RUMPHI and T.b. gambiense 348 BT in an acute, subacute and chronic infection model respectively, we observed differences in parasite tropism for murine tissues during in vivo BLI. Ex vivo BLI on the brain confirmed central nervous system infection by all luminescent strains of T.b. brucei AnTaR 1, T.b. rhodesiense RUMPHI and T.b. gambiense 348 BT. We established a genetically and phenotypically diverse collection of bioluminescent T.b. brucei, T.b. gambiense and T.b. rhodesiense strains, including drug resistant strains. For in vivo BLI monitoring of murine infections, we recommend trypanosome strains transfected with red-shifted luciferase reporter genes, such as CBR and PpyRE9. Red-shifted luciferases can be detected with a higher sensitivity in vivo and at the same time they improve the spatial resolution of the parasites in the entire body due to the better kinetics of their substrate D-luciferin.

A Panel of Trypanosoma brucei Strains Tagged with Blue and Red-Shifted Luciferases for Bioluminescent Imaging in Murine Infection Models

PubMed Central

Van Reet, Nick; Van de Vyver, Hélène; Pyana, Patient Pati; Van der Linden, Anne Marie; Büscher, Philippe

2014-01-01

Background Genetic engineering with luciferase reporter genes allows monitoring Trypanosoma brucei (T.b.) infections in mice by in vivo bioluminescence imaging (BLI). Until recently, luminescent T.b. models were based on Renilla luciferase (RLuc) activity. Our study aimed at evaluating red-shifted luciferases for in vivo BLI in a set of diverse T.b. strains of all three subspecies, including some recently isolated from human patients. Methodology/Principal findings We transfected T.b. brucei, T.b. rhodesiense and T.b. gambiense strains with either RLuc, click beetle red (CBR) or Photinus pyralis RE9 (PpyRE9) luciferase and characterised their in vitro luciferase activity, growth profile and drug sensitivity, and their potential for in vivo BLI. Compared to RLuc, the red-shifted luciferases, CBR and PpyRE9, allow tracking of T.b. brucei AnTaR 1 trypanosomes with higher details on tissue distribution, and PpyRE9 allows detection of the parasites with a sensitivity of at least one order of magnitude higher than CBR luciferase. With CBR-tagged T.b. gambiense LiTaR1, T.b. rhodesiense RUMPHI and T.b. gambiense 348 BT in an acute, subacute and chronic infection model respectively, we observed differences in parasite tropism for murine tissues during in vivo BLI. Ex vivo BLI on the brain confirmed central nervous system infection by all luminescent strains of T.b. brucei AnTaR 1, T.b. rhodesiense RUMPHI and T.b. gambiense 348 BT. Conclusions/Significance We established a genetically and phenotypically diverse collection of bioluminescent T.b. brucei, T.b. gambiense and T.b. rhodesiense strains, including drug resistant strains. For in vivo BLI monitoring of murine infections, we recommend trypanosome strains transfected with red-shifted luciferase reporter genes, such as CBR and PpyRE9. Red-shifted luciferases can be detected with a higher sensitivity in vivo and at the same time they improve the spatial resolution of the parasites in the entire body due to the better kinetics of their substrate D-luciferin. PMID:25144573

Estimating tuberculosis incidence from primary survey data: a mathematical modeling approach

PubMed Central

Chadha, V. K.; Laxminarayan, R.; Arinaminpathy, N.

2017-01-01

SUMMARY BACKGROUND: There is an urgent need for improved estimations of the burden of tuberculosis (TB). OBJECTIVE: To develop a new quantitative method based on mathematical modelling, and to demonstrate its application to TB in India. DESIGN: We developed a simple model of TB transmission dynamics to estimate the annual incidence of TB disease from the annual risk of tuberculous infection and prevalence of smear-positive TB. We first compared model estimates for annual infections per smear-positive TB case using previous empirical estimates from China, Korea and the Philippines. We then applied the model to estimate TB incidence in India, stratified by urban and rural settings. RESULTS: Study model estimates show agreement with previous empirical estimates. Applied to India, the model suggests an annual incidence of smear-positive TB of 89.8 per 100 000 population (95%CI 56.8–156.3). Results show differences in urban and rural TB: while an urban TB case infects more individuals per year, a rural TB case remains infectious for appreciably longer, suggesting the need for interventions tailored to these different settings. CONCLUSIONS: Simple models of TB transmission, in conjunction with necessary data, can offer approaches to burden estimation that complement those currently being used. PMID:28284250

Current and developing therapies for the treatment of multi drug resistant tuberculosis (MDR-TB) in India.

PubMed

Muniyandi, Malaisamy; Ramachandran, Rajeswari

2017-09-01

India accounts for 25% of the global burden of MDR-TB. In 2016, the India's Revised National TB Control Programme reported a success rate of 46% among 19,298 MDR-TB patients treated under the programme. This suboptimal treatment outcome warrants an urgent need for newer drugs and newer regimens in the treatment of MDR-TB. India requires new shorter, cheap, safe and effective anti-TB regimen to treat MDR-TB. Areas covered: We used different search strategies to obtain relevant literature from PubMed, on Indian experiences of developing therapies for the treatment of MDR-TB. Further information from the Central TB Division Government of India on programmatic management of resistant TB was collected. Expert opinion: In 2016 WHO recommended a shorter MDR-TB regimen of 9-12 months (4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E /5 Mfx-Cfz-Z-E) may be used instead of longer regimens. Currently, conducting trials involving newer drugs such as bedaquiline, have been proposed. The regimen will be of a shorter duration containing isoniazid, prothionamide, bedaquiline, levofloxacin, ciprofloxacin, ethambutol and pyrazinamide (STREAM regimen). To successfully treat MDR-TB one requires new classes of antibiotic and newer diagnostic tests. This represents an enormous financial and technical challenge to the programme managers and policy makers.

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in Hiv-positive adults

PubMed Central

Shah, Maunank; Hanrahan, Colleen; Wang, Zhuo Yu; Dendukuri, Nandini; Lawn, Stephen D; Denkinger, Claudia M; Steingart, Karen R

2016-01-01

Background Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV-associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV-positive individuals, who have higher rates of extrapulmonary TB compared with HIV-negative individuals. The lateral flow urine lipoarabinomannan assay (LF-LAM) is a new, commercially available point-of-care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease. Objectives To assess the accuracy of LF-LAM for the diagnosis of active TB disease in HIV-positive adults who have signs and symptoms suggestive of TB (TB diagnosis).To assess the accuracy of LF-LAM as a screening test for active TB disease in HIV-positive adults irrespective of signs and symptoms suggestive of TB (TB screening). Search methods We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI-EXPANDED, from 1900), Conference Proceedings Citation Index-Science (CPCI-S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861). Selection criteria Eligible study types included randomized controlled trials, cross-sectional studies, and cohort studies that determined LF-LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were evaluated for TB, and a lower quality reference standard was one in which only one specimen type was evaluated for TB. Participants were HIV-positive people aged 15 years and older. Data collection and analysis Two review authors independently extracted data from each included study using a standardized form. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We evaluated the test at two different cut-offs: (grade 1 or 2, based on the reference card scale of five intensity bands). Most analyses used grade 2, the manufacturer's currently recommended cut-off for positivity. We carried out meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and estimated the models using a Bayesian approach. We determined accuracy of LF-LAM combined with sputum microscopy or Xpert® MTB/RIF. In addition, we explored the influence of CD4 count on the accuracy estimates. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results We included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were cross-sectional or cohort studies. Studies for TB diagnosis were largely conducted among inpatients (median CD4 range 71 to 210 cells per µL) and studies for TB screening were largely conducted among outpatients (median CD4 range 127 to 437 cells per µL). All studies were conducted in low- or middle-income countries. Only two studies for TB diagnosis (33%) and one study for TB screening (17%) used a higher quality reference standard. LF-LAM for TB diagnosis (grade 2 cut-off): meta-analyses showed median pooled sensitivity and specificity (95% credible interval (CrI)) of 45% (29% to 63%) and 92% (80% to 97%), (five studies, 2313 participants, 35% with TB, low quality evidence). The pooled sensitivity of a combination of LF-LAM and sputum microscopy (either test positive) was 59% (47% to 70%), which represented a 19% (4% to 36%) increase over sputum microscopy alone, while the pooled specificity was 92% (73% to 97%), which represented a 6% (1% to 24%) decrease from sputum microscopy alone (four studies, 1876 participants, 38% with TB). The pooled sensitivity of a combination of LF-LAM and sputum Xpert® MTB/RIF (either test positive) was 75% (61% to 87%) and represented a 13% (1% to 37%) increase over Xpert® MTB/RIF alone. The pooled specificity was 93% (81% to 97%) and represented a 4% (1% to 16%) decrease from Xpert® MTB/RIF alone (three studies, 909 participants, 36% with TB). Pooled sensitivity and specificity of LF-LAM were 56% (41% to 70%) and 90% (81% to 95%) in participants with a CD4 count of less than or equal to 100 cells per µL (five studies, 859 participants, 47% with TB) versus 26% (16% to 46%) and 92% (78% to 97%) in participants with a CD4 count greater than 100 cells per µL (five studies, 1410 participants, 30% with TB). LF-LAM for TB screening (grade 2 cut-off): for individual studies, sensitivity estimates (95% CrI) were 44% (30% to 58%), 28% (16% to 42%), and 0% (0% to 71%) and corresponding specificity estimates were 95% (92% to 97%), 94% (90% to 97%), and 95% (92% to 97%) (three studies, 1055 participants, 11% with TB, very low quality evidence). There were limited data for additional analyses. The main limitations of the review were the use of a lower quality reference standard in most included studies, and the small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution. Authors' conclusions We found that LF-LAM has low sensitivity to detect TB in adults living with HIV whether the test is used for diagnosis or screening. For TB diagnosis, the combination of LF-LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. In HIV-positive individuals with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB. PLAIN LANGUAGE SUMMARY The lateral flow urine lipoarabinomannan (LF-LAM) test for diagnosis of tuberculosis in people living with human immunodeficiency virus (HIV) Background Tuberculosis (TB) is a common cause of death in people with human immunodeficiency virus (HIV) infection, but diagnosis is difficult, and depends on testing for TB in the sputum and other sites, which may take weeks to give results. A rapid and accurate point-of-care test could reduce delays in diagnosis, allow treatment to start promptly, and improve linkage between diagnosis and treatment. Test evaluated by this review The lateral flow urine lipoarabinomannan assay (LF-LAM, Alere Determine™ TB LAM Ag, Alere Inc, Waltham, MA, USA) is a commercially available point-of-care test for active TB (pulmonary and extrapulmonary TB). The test detects lipoarabinomannan (LAM), a component of the bacterial cell walls, which is present in some people with active TB. The test is performed by placing urine on one end of a test strip, with results appearing as a line (that is, a band) on the strip if TB is present. The test is simple, requires no special equipment, and shows results in 25 minutes. During the period we conducted the review, the manufacturer issued new recommendations for defining a positive test. We collected data based on both the original and the new recommendations Objectives We aimed to see how accurately LF-LAM diagnosed TB in people living with HIV with TB symptoms, and how accurately LF-LAM diagnosed TB in people living with HIV being screened for TB whether or not they had TB symptoms. Main results We examined evidence up to 5 February 2015 and included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were conducted in low- or middle-income countries. Quality of the evidence We assessed quality by describing how participants were selected for the studies, details of the test and reference standards (the benchmark test), and study flow and timing, using the standard QUADAS-2 approach. Few studies used multiple types of specimens for the reference standard (higher quality standard) and most relied on sputum culture alone (lower quality standard), which may have affected results. What do the results mean? In a population of 1000 HIV-positive individuals with TB symptoms, where 300 actually have TB, the test will correctly identify 135 people as having TB, but miss the remaining 165 people; for the 700 people who do not have TB, the test will correctly identify 644 people as not having TB, but will misclassify 56 as having TB. The sensitivity of the test is higher in people living with HIV with low CD4 cell counts who are at risk of life-threatening illnesses. In patients with a CD4 ≤ 100 cells per µL, LF-LAM sensitivity was 56% (41% to 70%) versus 26% (16% to 46%) in patients with a CD4 count = 100 cells per µL. If the test is used in screening HIV-positive people for TB, in a population of 1000 where 10 actually have TB, LF-LAM will correctly identify none of the 10, or up to four of the 10; on the other hand, the test will miss six to 10 people with TB; in the remaining 990 who do not have TB, the test will correctly identify 931 to 941 people as not having TB while misclassifying 49 to 59 as having TB. Limitations The main limitations of the review were the use of a lower quality reference standard in most included studies, and small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution. Conclusions In this Cochrane review, we found that LF-LAM, whether the test is used for diagnosis or screening, has low sensitivity to detect TB. However, in HIV-positive people with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB. PMID:27163343

Invariant NKT cells from HIV-1 or Mycobacterium tuberculosis-infected patients express an activated phenotype.

PubMed

Montoya, Carlos J; Cataño, Juan C; Ramirez, Zoraida; Rugeles, Maria T; Wilson, S Brian; Landay, Alan L

2008-04-01

The frequency, subsets and activation status of peripheral blood invariant NKT (iNKT) cells were evaluated in pulmonary tuberculosis (TB) patients and in chronically HIV-1-infected subjects. The absolute numbers of iNKT cells were significantly decreased in TB patients and in HIV-1+ individuals who were antiretroviral therapy naive or had detectable viremia despite receiving HAART. iNKT cell subset analysis demonstrated a decreased percentage of CD4(+) iNKT cells in HIV-1+ subjects, and a decreased percentage of double negative iNKT cells in TB patients. Peripheral blood iNKT cells from HIV-1+ and TB patients had significantly increased expression of CD69, CD38, HLA-DR, CD16, CD56, and CD62L. The expression of CD25 was significantly increased only on iNKT cells from TB patients. These findings indicate that peripheral blood iNKT cells in these two chronic infections show an up-regulated expression of activation markers, suggesting their role in the immune response to infection.

A Beneficial Effect of Low-Dose Aspirin in a Murine Model of Active Tuberculosis

PubMed Central

Kroesen, Vera Marie; Rodríguez-Martínez, Paula; García, Eric; Rosales, Yaiza; Díaz, Jorge; Martín-Céspedes, Montse; Tapia, Gustavo; Sarrias, Maria Rosa; Cardona, Pere-Joan; Vilaplana, Cristina

2018-01-01

An excessive, non-productive host-immune response is detrimental in active, chronic tuberculosis (TB) disease as it typically leads to tissue damage. Given their anti-inflammatory effect, non-steroidal anti-inflammatory drugs can potentially attenuate excessive inflammation in active TB disease. As such, we investigated the prophylactic and therapeutic effect of low-dose aspirin (LDA) (3 mg/kg/day), either alone or in combination with common anti-TB treatment or BCG vaccination, on disease outcome in an experimental murine model of active TB. Survival rate, bacillary load (BL) in lungs, and lung pathology were measured. The possible mechanism of action of LDA on the host’s immune response was also evaluated by measuring levels of CD5L/AIM, selected cytokines/chemokines and other inflammatory markers in serum and lung tissue. LDA increased survival, had anti-inflammatory effects, reduced lung pathology, and decreased bacillary load in late-stage TB disease. Moreover, in combination with common anti-TB treatment, LDA enhanced survival and reduced lung pathology. Results from the immunological studies suggest the anti-inflammatory action of LDA at both a local and a systemic level. Our results showed a systemic decrease in neutrophilic recruitment, decreased levels of acute-phase reaction cytokines (IL-6, IL-1β, and TNF-α) at late stage and a delay in the decrease in T cell response (in terms of IFN-γ, IL-2, and IL-10 serum levels) that occurs during the course of Mycobacterium tuberculosis infection. An anti-inflammatory milieu was detected in the lung, with less neutrophil recruitment and lower levels of tissue factor. In conclusion, LDA may be beneficial as an adjunct to standard anti-TB treatment in the later stage of active TB by reducing excess, non-productive inflammation, while enhancing Th1-cell responses for elimination of the bacilli. PMID:29740435

A rapid assessment and response approach to review and enhance Advocacy, Communication and Social Mobilisation for Tuberculosis control in Odisha state, India

PubMed Central

2011-01-01

Background Tuberculosis remains a major public health problem in India with the country accounting for 1 in 5 of all TB cases reported globally. An advocacy, communication and social mobilisation project for Tuberculosis control was implemented and evaluated in Odisha state of India. The purpose of the study was to identify the impact of project interventions including the use of 'Interface NGOs' and involvement of community groups such as women's self-help groups, local government bodies, village health sanitation committees, and general health staff in promoting TB control efforts. Methods The study utilized a rapid assessment and response (RAR) methodology. The approach combined both qualitative field work approaches, including semi-structured interviews and focus group discussions with empirical data collection and desk research. Results Results revealed that a combination of factors including the involvement of Interface NGOs, coupled with increased training and engagement of front line health workers and community groups, and dissemination of community based resources, contributed to improved awareness and knowledge about TB in the targeted districts. Project activities also contributed towards improving health worker and community effectiveness to raise the TB agenda, and improved TB literacy and treatment adherence. Engagement of successfully treated patients also assisted in reducing community stigma and discrimination. Conclusion The expanded use of advocacy, communication and social mobilisation activities in TB control has resulted in a number of benefits. These include bridging pre-existing gaps between the health system and the community through support and coordination of general health services stakeholders, NGOs and the community. The strategic use of 'tailored messages' to address specific TB problems in low performing areas also led to more positive behavioural outcomes and improved efficiencies in service delivery. Implications for future studies are that a comprehensive and well planned range of ACSM activities can enhance TB knowledge, attitudes and behaviours while also mobilising specific community groups to build community efficacy to combat TB. The use of rapid assessments combined with other complementary evaluation approaches can be effective when reviewing the impact of TB advocacy, communication and social mobilisation activities. PMID:21663623

A rapid assessment and response approach to review and enhance advocacy, communication and social mobilisation for tuberculosis control in Odisha state, India.

PubMed

Kamineni, Vishnu Vardhan; Turk, Tahir; Wilson, Nevin; Satyanarayana, Srinath; Chauhan, Lakbir Singh

2011-06-10

Tuberculosis remains a major public health problem in India with the country accounting for 1 in 5 of all TB cases reported globally. An advocacy, communication and social mobilisation project for Tuberculosis control was implemented and evaluated in Odisha state of India. The purpose of the study was to identify the impact of project interventions including the use of 'Interface NGOs' and involvement of community groups such as women's self-help groups, local government bodies, village health sanitation committees, and general health staff in promoting TB control efforts. The study utilized a rapid assessment and response (RAR) methodology. The approach combined both qualitative field work approaches, including semi-structured interviews and focus group discussions with empirical data collection and desk research. Results revealed that a combination of factors including the involvement of Interface NGOs, coupled with increased training and engagement of front line health workers and community groups, and dissemination of community based resources, contributed to improved awareness and knowledge about TB in the targeted districts. Project activities also contributed towards improving health worker and community effectiveness to raise the TB agenda, and improved TB literacy and treatment adherence. Engagement of successfully treated patients also assisted in reducing community stigma and discrimination. The expanded use of advocacy, communication and social mobilisation activities in TB control has resulted in a number of benefits. These include bridging pre-existing gaps between the health system and the community through support and coordination of general health services stakeholders, NGOs and the community. The strategic use of 'tailored messages' to address specific TB problems in low performing areas also led to more positive behavioural outcomes and improved efficiencies in service delivery. Implications for future studies are that a comprehensive and well planned range of ACSM activities can enhance TB knowledge, attitudes and behaviours while also mobilising specific community groups to build community efficacy to combat TB. The use of rapid assessments combined with other complementary evaluation approaches can be effective when reviewing the impact of TB advocacy, communication and social mobilisation activities.

IFNγ-producing CD4+ T lymphocytes: the double-edged swords in tuberculosis.

PubMed

Kumar, Pawan

2017-12-01

IFNγ-producing CD4 + T cells (IFNγ + CD4 + T cells) are the key orchestrators of protective immunity against Mycobacterium tuberculosis (Mtb). Primarily, these cells act by enabling Mtb-infected macrophages to enforce phagosome-lysosome fusion, produce reactive nitrogen intermediates (RNIs), and activate autophagy pathways. However, TB is a heterogeneous disease and a host of clinical and experimental findings has also implicated IFNγ + CD4 + T cells in TB pathogenesis. High frequency of IFNγ + CD4 + T cells is the most invariable feature of the active disease. Active TB patients mount a heightened IFNγ + CD4 + T cell response to mycobacterial antigens and demonstrate an IFNγ-inducible transcriptomic signature. IFNγ + CD4 + T cells have also been shown to mediate TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) observed in a subset of antiretroviral therapy (ART)-treated HIV- and Mtb-coinfected people. The pathological face of IFNγ + CD4 + T cells during mycobacterial infection is further uncovered by studies in the animal model of TB-IRIS and in Mtb-infected PD-1 -/- mice. This manuscript encompasses the evidence supporting the dual role of IFNγ + CD4 + T cells during Mtb infection and sheds light on immune mechanisms involved in protection versus pathogenesis.

Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study

PubMed Central

Anderson, Suzanne T.; Bangani, Nonzwakazi; Banwell, Claire M.; Brent, Andrew J.; Crampin, Amelia C.; Dockrell, Hazel M.; Eley, Brian; Heyderman, Robert S.; Hibberd, Martin L.; Kern, Florian; Langford, Paul R.; Ling, Ling; Mendelson, Marc; Ottenhoff, Tom H.; Zgambo, Femia; Wilkinson, Robert J.; Coin, Lachlan J.; Levin, Michael

2013-01-01

Background A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test. Methods and Findings Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87–100]; specificity 90%, 95% CI [80–97]) and TB from OD (sensitivity 93%, 95% CI [83–100]; specificity 88%, 95% CI [74–97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85–100]; specificity 94%, 95% CI [84–100]) and OD patients (sensitivity 100%, 95% CI [100–100]; specificity 96%, 95% CI [93–100]). Limitations of our study include the use of only culture confirmed TB patients, and the potential that TB may have been misdiagnosed in a small proportion of OD patients despite the extensive clinical investigation used to assign each patient to their diagnostic group. Conclusions In our study, blood transcriptional signatures distinguished TB from other conditions prevalent in HIV-infected and -uninfected African adults. Our DRS, based on these signatures, could be developed as a test for TB suitable for use in HIV endemic countries. Further evaluation of the performance of the signatures and DRS in prospective populations of patients with symptoms consistent with TB will be needed to define their clinical value under operational conditions. Please see later in the article for the Editors' Summary PMID:24167453

Drug-resistant tuberculosis in Mumbai, India: An agenda for operations research

PubMed Central

Mistry, Nerges; Tolani, Monica; Osrin, David

2012-01-01

Operations research (OR) is well established in India and is also a prominent feature of the global and local agendas for tuberculosis (TB) control. India accounts for a quarter of the global burden of TB and of new cases. Multidrug-resistant TB is a significant problem in Mumbai, India’s most populous city, and there have been recent reports of totally resistant TB. Much thought has been given to the role of OR in addressing programmatic challenges, by both international partnerships and India’s Revised National TB Control Programme. We attempt to summarize the major challenges to TB control in Mumbai, with an emphasis on drug resistance. Specific challenges include diagnosis of TB and defining cure, detecting drug resistant TB, multiple sources of health care in the private, public and informal sectors, co-infection with human immunodeficiency virus (HIV) and a concurrent epidemic of non-communicable diseases, suboptimal prescribing practices, and infection control. We propose a local agenda for OR: modeling the effects of newer technologies, active case detection, and changes in timing of activities, and mapping hotspots and contact networks; modeling the effects of drug control, changing the balance of ambulatory and inpatient care, and adverse drug reactions; modeling the effects of integration of TB and HIV diagnosis and management, and preventive drug therapy; and modeling the effects of initiatives to improve infection control. PMID:24501697

Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis

PubMed Central

Andrade, Bruno B.; Kumar, Nathella Pavan; Amaral, Eduardo P.; Riteau, Nicolas; Mayer-Barber, Katrin D.; Tosh, Kevin W.; Maier, Nolan; Conceição, Elisabete L.; Kubler, Andre; Sridhar, Rathinam; Banurekha, Vaithilingam V.; Jawahar, Mohideen S.; Barbosa, Theolis; Manganiello, Vincent C.; Moss, Joel; Fontana, Joseph R.; Marciano, Beatriz E.; Sampaio, Elizabeth P.; Olivier, Kenneth N.; Holland, Steven M.; Jackson, Sharon H.; Moayeri, Mahtab; Leppla, Stephen; Sereti, Irini; Barber, Daniel L.; Nutman, Thomas B.; Babu, Subash; Sher, Alan

2015-01-01

Pulmonary tuberculosis (TB) is characterized by oxidative stress and lung tissue destruction by matrix metalloproteinases (MMP). The interplay between these distinct pathological processes and the implications for TB diagnosis and disease staging are poorly understood. Heme oxygenase-1 (HO-1) levels have been shown to distinguish active from latent as well as successfully treated Mycobacterium tuberculosis (Mtb) infection. MMP-1 expression is also associated with active TB. Here, we measured plasma levels of these two important biomarkers in distinct TB cohorts from India and Brazil. Patients with active TB expressed either very high levels of HO-1 and low levels of MMP-1 or the converse. Moreover, TB patients with either high HO-1 or MMP-1 levels displayed distinct clinical presentations as well as plasma inflammatory marker profiles. In contrast, in an exploratory North American study, inversely correlated expression of HO-1 and MMP-1 was not observed in patients with other non-tuberculous lung diseases. To assess possible regulatory interactions in the biosynthesis of these two enzymes at the cellular level, we studied expression of HO-1 and MMP-1 in Mtb-infected human and murine macrophages. We found that infection of macrophages with live virulent Mtb is required for robust induction of high levels of HO-1, but not MMP-1. In addition, we observed that carbon monoxide, a product of Mtb induced HO-1 activity, inhibits MMP-1 expression by suppressing c-Jun/AP-1 activation. These findings reveal a mechanistic link between oxidative stress and tissue remodeling that may find applicability in the clinical staging of TB patients. PMID:26268658

Increasing the structural coverage of tuberculosis drug targets.

PubMed

Baugh, Loren; Phan, Isabelle; Begley, Darren W; Clifton, Matthew C; Armour, Brianna; Dranow, David M; Taylor, Brandy M; Muruthi, Marvin M; Abendroth, Jan; Fairman, James W; Fox, David; Dieterich, Shellie H; Staker, Bart L; Gardberg, Anna S; Choi, Ryan; Hewitt, Stephen N; Napuli, Alberto J; Myers, Janette; Barrett, Lynn K; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W; Stacy, Robin; Stewart, Lance J; Edwards, Thomas E; Van Voorhis, Wesley C; Myler, Peter J

2015-03-01

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Increasing the structural coverage of tuberculosis drug targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baugh, Loren; Phan, Isabelle; Begley, Darren W.

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structuresmore » would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PS APF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less

Increasing the structural coverage of tuberculosis drug targets

DOE PAGES

Baugh, Loren; Phan, Isabelle; Begley, Darren W.; ...

2014-12-19

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structuresmore » would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PS APF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less

Increasing the Structural Coverage of Tuberculosis Drug Targets

PubMed Central

Baugh, Loren; Phan, Isabelle; Begley, Darren W.; Clifton, Matthew C.; Armour, Brianna; Dranow, David M.; Taylor, Brandy M.; Muruthi, Marvin M.; Abendroth, Jan; Fairman, James W.; Fox, David; Dieterich, Shellie H.; Staker, Bart L.; Gardberg, Anna S.; Choi, Ryan; Hewitt, Stephen N.; Napuli, Alberto J.; Myers, Janette; Barrett, Lynn K.; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W.; Stacy, Robin; Stewart, Lance J.; Edwards, Thomas E.; Van Voorhis, Wesley C.; Myler, Peter J.

2015-01-01

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. PMID:25613812

Accelerating TB notification from the private health sector in Delhi, India.

PubMed

Kundu, Debashish; Chopra, Kamal; Khanna, Ashwani; Babbar, Neeti; Padmini, T J

2016-01-01

In India, almost half of all patients with tuberculosis (TB) seek care in the private sector as the first point of care. The national programme is unable to support such TB patients and facilitate effective treatment, as there is no information on TB and Multi or Extensively Drug Resistant TB (M/XDR-TB) diagnosis and treatment in private sector. To improve this situation, Government of India declared TB a notifiable disease for establishing TB surveillance system, to extend supportive mechanism for TB treatment adherence and standardised practices in the private sector. But TB notification from the private sector is a challenge and still a lot needs to be done to accelerate TB notification. Delhi State TB Control Programme had taken initiatives for improving notification of TB cases from the private sector in 2014. Key steps taken were to constitute a state level TB notification committee to oversee the progress of TB notification efforts in the state and direct 'one to one' sensitisation of private practitioners (PPs) (in single PP's clinic, corporate hospitals and laboratories) by the state notification teams with the help of available tools for sensitising the PP on TB notification - TB Notification Government Order, Guidance Tool for TB Notification and Standards of TB Care in India. As a result of focussed state level interventions, without much external support, there was an accelerated notification of TB cases from the private sector. TB notification cases from the private sector rose from 341 (in 2013) to 4049 (by the end of March 2015). Active state level initiatives have led to increase in TB case notification. Copyright © 2016 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

Predicting treatment failure, death and drug resistance using a computed risk score among newly diagnosed TB patients in Tamaulipas, Mexico.

PubMed

Abdelbary, B E; Garcia-Viveros, M; Ramirez-Oropesa, H; Rahbar, M H; Restrepo, B I

2017-10-01

The purpose of this study was to develop a method for identifying newly diagnosed tuberculosis (TB) patients at risk for TB adverse events in Tamaulipas, Mexico. Surveillance data between 2006 and 2013 (8431 subjects) was used to develop risk scores based on predictive modelling. The final models revealed that TB patients failing their treatment regimen were more likely to have at most a primary school education, multi-drug resistance (MDR)-TB, and few to moderate bacilli on acid-fast bacilli smear. TB patients who died were more likely to be older males with MDR-TB, HIV, malnutrition, and reporting excessive alcohol use. Modified risk scores were developed with strong predictability for treatment failure and death (c-statistic 0·65 and 0·70, respectively), and moderate predictability for drug resistance (c-statistic 0·57). Among TB patients with diabetes, risk scores showed moderate predictability for death (c-statistic 0·68). Our findings suggest that in the clinical setting, the use of our risk scores for TB treatment failure or death will help identify these individuals for tailored management to prevent these adverse events. In contrast, the available variables in the TB surveillance dataset are not robust predictors of drug resistance, indicating the need for prompt testing at time of diagnosis.

Determining quantitative targets for public funding of tuberculosis research and development

PubMed Central

2013-01-01

South Africa’s expenditure on tuberculosis (TB) research and development (R&D) is insignificant relative to both its disease burden and the expenditure of some comparator countries with a minimal TB incidence. In 2010, the country had the second highest TB incidence rate in the world (796 per 100,000 population), and the third highest number of new TB cases (490,000 or 6% of the global total). Although it has a large TB treatment program (about $588 million per year), TB R&D funding is small both in absolute terms and relative to its total R&D expenditure. Given the risk and the high cost associated with drug discovery R&D, such neglect may make strategic sense. However in this analysis it is shown that TB R&D presents a unique opportunity to the national treasuries of all high-burden countries. Using two separate estimation methods (global justice and return on investment), it is concluded that most countries, including South Africa, are under-investing in TB R&D. Specific investment targets for a range of countries, particularly in areas of applied research, are developed. This work supports the outcome of the World Health Organization’s Consultative Expert Working Group on Research and Development: Financing and Coordination, which has called for “a process leading to the negotiation of a binding agreement on R&D relevant to the health needs of developing countries”. PMID:23496963

Caring for the carer: a systematic review of pure technology-based cognitive behavioral therapy (TB-CBT) interventions for dementia carers.

PubMed

Scott, Jennifer L; Dawkins, Sarah; Quinn, Michael G; Sanderson, Kristy; Elliott, Kate-Ellen J; Stirling, Christine; Schüz, Ben; Robinson, Andrew

2016-08-01

Face-to-face delivery of CBT is not always optimal or practical for informal dementia carers (DCs). Technology-based formats of CBT delivery (TB-CBT) have been developed with the aim to improve client engagement and accessibility, and lower delivery costs, and offers potential benefits for DCs. However, research of TB-CBT for DCs has maintained heavy reliance on therapist involvement. The efficacy of pure TB-CBT interventions for DCs is not currently established Methods: A systematic review of trials of pure TB-CBT intervention for DCs from 1995 was conducted. PsycINFO, Cochrane Reviews, Scopus and MedLine databases were searched using key terms related to CBT, carers and dementia. Four hundred and forty two articles were identified, and inclusion/exclusion criteria were applied; studies were only retained if quantitative data was available, and there was no active therapist contact. Four articles were retained; two randomized and two waitlist control trials. Methodological and reporting quality was assessed. Meta-analyses were conducted for the outcome measures of caregiver depression. Meta-analysis revealed small significant post-intervention effects of pure TB-CBT interventions for depression; equivalent to face-to-face interventions. However, there is no evidence regarding long-term efficacy of pure TB-CBT for DCs. The systematic review further identified critical methodological and reporting shortcomings pertaining to these trials Conclusions: Pure TB-CBT interventions may offer a convenient, economical method for delivering psychological interventions to DCs. Future research needs to investigate their long-term efficacy, and consider potential moderating and mediating factors underpinning the mechanisms of effect of these programs. This will help to provide more targeted interventions to this underserviced population.

Clinicopathological correlates in HIV seropositive tuberculosis cases presenting with jaundice after initiating antiretroviral therapy with a structured review of the literature.

PubMed

Barr, David A; Ramdial, Pravistadevi K

2012-10-14

The development of jaundice after initiation of HAART in HIV-TB co-infected patients is a challenging presentation in resource constrained settings, and is often attributed to drug induced liver injury (DILI).Some investigators have described hepatic tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) as a cause of liver disease in patients initiating HAART, which could also cause jaundice. We report the clinical and histopathological features of five HIV-TB co-infected patients presenting with a syndrome of jaundice, tender hepatomegaly, bile canalicular enzyme rise and return of constitutional symptoms within 8 weeks of initiation of highly active antiretroviral therapy (HAART) for advanced HIV infection at a rural clinic in KwaZulu Natal, South Africa.All five patients had been diagnosed with tuberculosis infection prior to HAART initiation and were on antituberculous medication at time of developing jaundice. There was evidence of multiple aetiologies of liver injury in all patients. However, based on clinical course and pathological findings, predominant hepatic injury was thought to be drug induced in one case and hepatic tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) in the other four.In these later 4 patients, liver biopsy findings included necrotising and non-necrotising granulomatous inflammation in the lobules and portal tracts. The granulomas demonstrated - in addition to epithelioid histiocytes and Langhans giant cells - neutrophils, plasma cells and large numbers of lymphocytes, which are not features of a conventional untreated tuberculous response. In this high TB prevalent, low resource setting, TB-IRIS may be an important cause of jaundice post-HAART initiation. Clinicopathological correlation is essential for optimal diagnosis. Further multi-organ based histopathological studies in the context of immune reconstitution would be useful to clinicians in low resource settings dealing with this challenging presentation.

Classification of worldwide bovine tuberculosis risk factors in cattle: a stratified approach

PubMed Central

Humblet, Marie-France; Boschiroli, Maria Laura; Saegerman, Claude

2009-01-01

The worldwide status of bovine tuberculosis (bTB) as a zoonosis remains of great concern. This article reviews the main risk factors for bTB in cattle based on a three-level classification: animal, herd and region/country level. A distinction is also made, whenever possible, between situations in developed and developing countries as the difference of context might have consequences in terms of risk of bTB. Recommendations are suggested to animal health professionals and scientists directly involved in the control and prevention of bTB in cattle. The determination of Millenium Development Goals for bTB is proposed to improve the control/eradication of the disease worldwide. PMID:19497258

The WHO's new End TB Strategy in the post-2015 era of the Sustainable Development Goals.

PubMed

Lönnroth, Knut; Raviglione, Mario

2016-03-01

The WHO's new End TB Strategy 2016-2035 has evolved from previous global strategies to respond to old and new challenges and take advantage of new opportunities. It frames the global fight against TB as a development, social justice and human rights issue, while re-emphasizing the public health and clinical fundaments of TB care and prevention. In this commentary, we outline how TB prevention, care and control will both benefit from and contribute to the achievement of the new Sustainable Development Goals that were recently adopted at the United Nations. © The author 2016. The World Health Organization has granted Oxford University Press permission for the reproduction of this article.

Development of integrated surveillance systems for the management of tuberculosis in New Zealand wildlife.

PubMed

Anderson, D P; Ramsey, D S L; de Lisle, G W; Bosson, M; Cross, M L; Nugent, G

2015-06-01

Disease surveillance for the management of bovine tuberculosis (TB) in New Zealand has focussed, to a large extent, on the development of tools specific for monitoring Mycobacterium bovis infection in wildlife. Diagnostic techniques have been modified progressively over 30 years of surveillance of TB in wildlife, from initial characterisation of gross TB lesions in a variety of wildlife, through development of sensitive culture techniques to identify viable mycobacteria, to molecular identification of individual M. bovis strains. Of key importance in disease surveillance has been the elucidation of the roles that different wildlife species play in the transmission of infection, specifically defining brushtail possums (Trichosurus vulpecula) as true maintenance hosts compared to those that are predominantly spillover hosts, but which may serve as useful sentinel species to indicate TB persistence. Epidemiological modelling has played a major role in TB surveillance, initially providing the theoretical support for large-scale possum population control and setting targets at which control effort should be deployed to ensure disease eradication. As TB prevalence in livestock and wildlife declined throughout the 2000s, more varied field tools were developed to gather surveillance data from the diminishing possum populations, and to provide information on changing TB prevalence. Accordingly, ever more precise (but disparate) surveillance information began to be integrated into multi-faceted decision-assist models to support TB management decisions, particularly to provide informed parameters at which control effort could be halted, culminating in the Proof of Freedom modelling framework that now allows an area to be declared TB-free within chosen confidence limits. As New Zealand moves from large-scale TB control to regional eradication of disease in the coming years, further integrative models will need to be developed to support management decisions, based on combined field data of possum and TB prevalence, sentinel information, risk assessment in relation to financial benefits, and changing political and environmental needs.

Roles of laboratories and laboratory systems in effective tuberculosis programmes.

PubMed

Ridderhof, John C; van Deun, Armand; Kam, Kai Man; Narayanan, P R; Aziz, Mohamed Abdul

2007-05-01

Laboratories and laboratory networks are a fundamental component of tuberculosis (TB) control, providing testing for diagnosis, surveillance and treatment monitoring at every level of the health-care system. New initiatives and resources to strengthen laboratory capacity and implement rapid and new diagnostic tests for TB will require recognition that laboratories are systems that require quality standards, appropriate human resources, and attention to safety in addition to supplies and equipment. To prepare the laboratory networks for new diagnostics and expanded capacity, we need to focus efforts on strengthening quality management systems (QMS) through additional resources for external quality assessment programmes for microscopy, culture, drug susceptibility testing (DST) and molecular diagnostics. QMS should also promote development of accreditation programmes to ensure adherence to standards to improve both the quality and credibility of the laboratory system within TB programmes. Corresponding attention must be given to addressing human resources at every level of the laboratory, with special consideration being given to new programmes for laboratory management and leadership skills. Strengthening laboratory networks will also involve setting up partnerships between TB programmes and those seeking to control other diseases in order to pool resources and to promote advocacy for quality standards, to develop strategies to integrate laboratories functions and to extend control programme activities to the private sector. Improving the laboratory system will assure that increased resources, in the form of supplies, equipment and facilities, will be invested in networks that are capable of providing effective testing to meet the goals of the Global Plan to Stop TB.

Exploratory Study on Plasma Immunomodulator and Antibody Profiles in Tuberculosis Patients

PubMed Central

Ravindran, Resmi; Krishnan, Viswanathan V.; Khanum, Azra; Luciw, Paul A.

2013-01-01

Host immune responses to Mycobacterium tuberculosis are generally able to contain infection and maintain a delicate balance between protection and immunopathology. A shift in this balance appears to underlie active disease observed in about 10% of infected individuals. Effects of local inflammation, combined with anti-M. tuberculosis systemic immune responses, are directly detectable in peripheral circulation, without ex vivo stimulation of blood cells or biopsy of the affected organs. We studied plasma immunomodulator and antibody biomarkers in patients with active pulmonary tuberculosis (TB) by a combination of multiplex microbead immunoassays and computational tools for data analysis. Plasma profiles of 10 immunomodulators and antibodies against eight M. tuberculosis antigens (previously reported by us) were examined in active pulmonary TB patients in a country where TB is endemic, Pakistan. Multiplex analyses were performed on samples from apparently healthy individuals without active TB from the same community as the TB patients to establish the assay baselines for all analytes. Over 3,000 data points were collected from patients (n = 135) and controls (n = 37). The data were analyzed by multivariate and computer-assisted cluster analyses to reveal patterns of plasma immunomodulators and antibodies. This study shows plasma profiles that in most patients represented either strong antibody or strong immunomodulator biomarkers. Profiling of a combination of both immunomodulators and antibodies described here may be valuable for the analysis of host immune responses in active TB in countries where the disease is endemic. PMID:23761664

Evaluating the electronic tuberculosis register surveillance system in Eden District, Western Cape, South Africa, 2015.

PubMed

Mlotshwa, Mandla; Smit, Sandra; Williams, Seymour; Reddy, Carl; Medina-Marino, Andrew

2017-01-01

Tuberculosis (TB) surveillance data are crucial to the effectiveness of National TB Control Programs. In South Africa, few surveillance system evaluations have been undertaken to provide a rigorous assessment of the platform from which the national and district health systems draws data to inform programs and policies. Evaluate the attributes of Eden District's TB surveillance system, Western Cape Province, South Africa. Data quality, sensitivity and positive predictive value were assessed using secondary data from 40,033 TB cases entered in Eden District's ETR.Net from 2007 to 2013, and 79 purposively selected TB Blue Cards (TBCs), a medical patient file and source document for data entered into ETR.Net. Simplicity, flexibility, acceptability, stability and usefulness of the ETR.Net were assessed qualitatively through interviews with TB nurses, information health officers, sub-district and district coordinators involved in the TB surveillance. TB surveillance system stakeholders report that Eden District's ETR.Net system was simple, acceptable, flexible and stable, and achieves its objective of informing TB control program, policies and activities. Data were less complete in the ETR.Net (66-100%) than in the TBCs (76-100%), and concordant for most variables except pre-treatment smear results, antiretroviral therapy (ART) and treatment outcome. The sensitivity of recorded variables in ETR.Net was 98% for gender, 97% for patient category, 93% for ART, 92% for treatment outcome and 90% for pre-treatment smear grading. Our results reveal that the system provides useful information to guide TB control program activities in Eden District. However, urgent attention is needed to address gaps in clinical recording on the TBC and data capturing into the ETR.Net system. We recommend continuous training and support of TB personnel involved with TB care, management and surveillance on TB data recording into the TBCs and ETR.Net as well as the implementation of a well-structured quality control and assurance system.

Active pulmonary tuberculosis case detection and treatment among floating population in China: an effective pilot.

PubMed

Li, Xinxu; Zhang, Hui; Jiang, Shiwen; Wang, Jia; Liu, Xiaoqiu; Li, Weibin; Yao, Hongyan; Wang, Lixia

2010-12-01

China has more and more floating population because of reform and opening-up. As one of the high burden countries in tuberculosis (TB) control in the world, China has to face more challenges about the TB case detection and treatment among floating population in China. Aim to evaluate the effect of case detection and treatment of the Floating Population TB Control Pilot Project from Global Fund Round Five (GFR5) TB Control Program in China. During October 2006 to September 2008, the pilot project was implemented gradually in 60 counties in Tianjin, Shanghai, Jiangsu, Zhejiang, Fujian, Shandong and Guangdong. All quarterly reports of the pilot project were collected, and these materials were summarized and analyzed. In seven coastal provinces, 19,584 active pulmonary TB (PTB) cases were registered among floating population in 2 years. Among the active PTB cases, 87.2% were 15-45 years old, and 62.8% were male. In second year, 15,629 active PTB cases were registered, and the overall registration rate was 68 per 100,000 people. DOT treatments were provided for 18,125 active PTB cases in 2 years, and overall DOT treatment rate was 92.6%. There were 3,955 active PTB cases registered in first year, and the overall cure rate was 86.0%. Through the implementation of the pilot project, the TB case detection and treatment among floating population have been enhanced in pilot areas of China. The useful experience and results from the pilot project have been being gradually generalized nationally.

Outcomes analysis of new entrant screening for active tuberculosis in Heathrow and Gatwick airports, United Kingdom 2009/2010.

PubMed

Severi, Ettore; Maguire, Helen; Ihekweazu, Chikwe; Bickler, Graham; Abubakar, Ibrahim

2016-04-22

In 2012, the United Kingdom (UK) Government announced that the new entrant screening for active tuberculosis (TB) in Heathrow and Gatwick airports would end. Our study objective was to estimate screening yield and diagnostic accuracy, and identify those at risk of active TB after entry. We designed a retrospective cohort study and linked new entrants screened from June 2009 to September 2010 through probabilistic matching with UK Enhanced TB Surveillance (ETS) data (June 2009 to December 2010). Yield was the proportion of cases reported to ETS within three months of airport screening in the screened population. To estimate screening diagnostic accuracy we assessed sensitivity, specificity, positive and negative predictive values. Through Poisson regression we identified groups at increased risk of TB diagnosis after entry. We identified 200,199 screened entrants, of these 59 had suspected TB at screening and were reported within 3 months to ETS (yield = 0.03 %). Sensitivity was 26 %; specificity was 99.7 %; positive predictive value was 13.2 %; negative predictive value was 99.9 %. Overall, 350 entrants were reported in ETS. Persons from countries with annual TB incidence higher than 150 cases per 100,000 population and refugees and asylum seekers were at increased risk of TB diagnosis after entry (population attributable risk 77 and 3 % respectively). Airport screening has very low screening yields, sensitivity and positive predictive value. New entrants coming from countries with annual TB incidence higher than 150 per 100,000 population, refugees and asylum seekers should be prioritised at pre- or post-entry screening.

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults.

PubMed

Shah, Maunank; Hanrahan, Colleen; Wang, Zhuo Yu; Dendukuri, Nandini; Lawn, Stephen D; Denkinger, Claudia M; Steingart, Karen R

2016-05-10

Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV-associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV-positive individuals, who have higher rates of extrapulmonary TB compared with HIV-negative individuals. The lateral flow urine lipoarabinomannan assay (LF-LAM) is a new, commercially available point-of-care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease. To assess the accuracy of LF-LAM for the diagnosis of active TB disease in HIV-positive adults who have signs and symptoms suggestive of TB (TB diagnosis).To assess the accuracy of LF-LAM as a screening test for active TB disease in HIV-positive adults irrespective of signs and symptoms suggestive of TB (TB screening). We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI-EXPANDED, from 1900), Conference Proceedings Citation Index-Science (CPCI-S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861). Eligible study types included randomized controlled trials, cross-sectional studies, and cohort studies that determined LF-LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were evaluated for TB, and a lower quality reference standard was one in which only one specimen type was evaluated for TB. Participants were HIV-positive people aged 15 years and older. Two review authors independently extracted data from each included study using a standardized form. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We evaluated the test at two different cut-offs: (grade 1 or 2, based on the reference card scale of five intensity bands). Most analyses used grade 2, the manufacturer's currently recommended cut-off for positivity. We carried out meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and estimated the models using a Bayesian approach. We determined accuracy of LF-LAM combined with sputum microscopy or Xpert® MTB/RIF. In addition, we explored the influence of CD4 count on the accuracy estimates. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were cross-sectional or cohort studies. Studies for TB diagnosis were largely conducted among inpatients (median CD4 range 71 to 210 cells per µL) and studies for TB screening were largely conducted among outpatients (median CD4 range 127 to 437 cells per µL). All studies were conducted in low- or middle-income countries. Only two studies for TB diagnosis (33%) and one study for TB screening (17%) used a higher quality reference standard.LF-LAM for TB diagnosis (grade 2 cut-off): meta-analyses showed median pooled sensitivity and specificity (95% credible interval (CrI)) of 45% (29% to 63%) and 92% (80% to 97%), (five studies, 2313 participants, 35% with TB, low quality evidence). The pooled sensitivity of a combination of LF-LAM and sputum microscopy (either test positive) was 59% (47% to 70%), which represented a 19% (4% to 36%) increase over sputum microscopy alone, while the pooled specificity was 92% (73% to 97%), which represented a 6% (1% to 24%) decrease from sputum microscopy alone (four studies, 1876 participants, 38% with TB). The pooled sensitivity of a combination of LF-LAM and sputum Xpert® MTB/RIF (either test positive) was 75% (61% to 87%) and represented a 13% (1% to 37%) increase over Xpert® MTB/RIF alone. The pooled specificity was 93% (81% to 97%) and represented a 4% (1% to 16%) decrease from Xpert® MTB/RIF alone (three studies, 909 participants, 36% with TB). Pooled sensitivity and specificity of LF-LAM were 56% (41% to 70%) and 90% (81% to 95%) in participants with a CD4 count of less than or equal to 100 cells per µL (five studies, 859 participants, 47% with TB) versus 26% (16% to 46%) and 92% (78% to 97%) in participants with a CD4 count greater than 100 cells per µL (five studies, 1410 participants, 30% with TB).LF-LAM for TB screening (grade 2 cut-off): for individual studies, sensitivity estimates (95% CrI) were 44% (30% to 58%), 28% (16% to 42%), and 0% (0% to 71%) and corresponding specificity estimates were 95% (92% to 97%), 94% (90% to 97%), and 95% (92% to 97%) (three studies, 1055 participants, 11% with TB, very low quality evidence). There were limited data for additional analyses.The main limitations of the review were the use of a lower quality reference standard in most included studies, and the small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution. We found that LF-LAM has low sensitivity to detect TB in adults living with HIV whether the test is used for diagnosis or screening. For TB diagnosis, the combination of LF-LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. In HIV-positive individuals with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB.

Health worker perspectives on barriers to delivery of routine tuberculosis diagnostic evaluation services in Uganda: a qualitative study to guide clinic-based interventions.

PubMed

Cattamanchi, Adithya; Miller, Cecily R; Tapley, Asa; Haguma, Priscilla; Ochom, Emmanuel; Ackerman, Sara; Davis, J Lucian; Katamba, Achilles; Handley, Margaret A

2015-01-22

Studies of the quality of tuberculosis (TB) diagnostic evaluation of patients in high burden countries have generally shown poor adherence to international or national guidelines. Health worker perspectives on barriers to improving TB diagnostic evaluation are critical for developing clinic-level interventions to improve guideline implementation. We conducted structured, in-depth interviews with staff at six district-level health centers in Uganda to elicit their perceptions regarding barriers to TB evaluation. Interviews were transcribed, coded with a standardized framework, and analyzed to identify emergent themes. We used thematic analysis to develop a logic model depicting health system and contextual barriers to recommended TB evaluation practices. To identify possible clinic-level interventions to improve TB evaluation, we categorized findings into predisposing, enabling, and reinforcing factors as described by the PRECEDE model, focusing on potentially modifiable behaviors at the clinic-level. We interviewed 22 health center staff between February 2010 and November 2011. Participants identified key health system barriers hindering TB evaluation, including: stock-outs of drugs/supplies, inadequate space and infrastructure, lack of training, high workload, low staff motivation, and poor coordination of health center services. Contextual barrier challenges to TB evaluation were also reported, including the time and costs borne by patients to seek and complete TB evaluation, poor health literacy, and stigma against patients with TB. These contextual barriers interacted with health system barriers to contribute to sub-standard TB evaluation. Examples of intervention strategies that could address these barriers and are related to PRECEDE model components include: assigned mentors/peer coaching for new staff (targets predisposing factor of low motivation and need for support to conduct job duties); facilitated workshops to implement same day microscopy (targets enabling factor of patient barriers to completing TB evaluation), and recognition/incentives for good TB screening practices (targets low motivation and self-efficacy). Our findings suggest that health system and contextual barriers work together to impede TB diagnosis at health centers and, if not addressed, could hinder TB case detection efforts. Qualitative research that improves understanding of the barriers facing TB providers is critical to developing targeted interventions to improve TB care.

Generating Effective Facilitation Questions for Team-Building/Personal-Challenge Activities

ERIC Educational Resources Information Center

Gabbei, Ritchie

2004-01-01

Team-building/personal-challenge (TB/PC) activities have become popular ways to address students' interpersonal and intrapersonal skills and abilities associated with the affective domain. The outcomes associated with TB/PC activities are often best experienced and learned through the use of indirect methods of instruction. Typically, many…